WO2020077361A1

WO2020077361A1 - Compounds and methods of their use

Info

Publication number: WO2020077361A1
Application number: PCT/US2019/056318
Authority: WO
Inventors: Anders M. NAAR; Gerhard Wagner; Joy Nishikawa; Su Wu; Sara J. BUHRLAGE; Andras Pal BOESZOERMENYI; Haribabu Arthanari; Christoph GORGULLA
Original assignee: General Hospital Corp; Dana Farber Cancer Institute Inc; Harvard University
Current assignee: General Hospital Corp; Dana Farber Cancer Institute Inc; Harvard University
Priority date: 2018-10-12
Filing date: 2019-10-15
Publication date: 2020-04-16
Anticipated expiration: 2021-04-12

Abstract

Provided are agents capable of binding the KIX domain of CBP or MED15 to inhibit the binding between SREBP1 and the KIX domain of MED15 or CBP. Also provided are compositions containing the agents and methods of their use.

Description

COMPOUNDS AND METHODS OF THEIR USE

STATEMENT AS TO FEDERALLY FUNDED RESEARCH

This invention was made with government support under Grant No. NIH/R01 HL1 16391 , awarded by the National Institutes of Health. The government has certain rights in this invention.

FIELD OF THE INVENTION

The invention provides compounds, compositions containing them, and methods of their use.

BACKGROUND

Elevated de novo fatty acid biosynthesis (DNFA) is a hallmark metabolic adaptation in many cancers that supports survival, proliferation, and metastasis under adverse (e.g. anaerobic and nutrient- deficient) conditions.

Cancer cells progress to hyper-proliferative and ultimately malignant states while exhibiting a series of hallmark traits. Among these is elevated de novo fatty acid biosynthesis (DNFA), the metabolic conversion of carbohydrates into lipids. Because cancer cells prefer DNFA to fuel necessary membrane and energy production, elevated DNFA enzymes often correlate with advanced stage tumors. Most healthy adult cells, even those with high turnover, prefer circulating lipids for cellular needs. In adults, DNFA activity is restricted to tissues such as liver and adipose, predominately for energy storage, and even they can tolerate its inhibition. Fetuses rely on DNFA for rapid cell proliferation and tissue development. Robust DNFA activity is essential for embryonic development and even dietary fat cannot substitute for DNFA. Thus, cancer’s tendency to employ DNFA more closely resembles embryonic than adult cell behavior, which may offer an opportunity to advance the quest for cancer-specific

chemotherapies.

DNFA occurs in a catalytic cascade with the aid of several lipogenic enzymes, including acetyl- CoA carboxylase (ACACA), fatty acid synthase (FASN), and stearoyl-CoA desaturase (SCD). The substrate of DNFA, acetyl coenzyme A (CoA), is generated from citrate by ATP citrate lyase (ACLY) or from acetate by acyl-coenzyme A synthetase (ACSS2). Sterol regulatory element-binding protein 1 (SREBP1 ) directly regulates the transcription of DNFA enzymes by binding their gene promoters, and thus serves as the master regulator of cellular lipid production. Insulin and growth factor signaling stimulates SREBP1 activation in cancer through the PI3K/AKT pathway. Activated SREBP1 migrates into the nucleus, binds to sterol regulatory elements (SRE) in the lipogenic gene promoters and further support tumor growth. In the context of cancer treatment, the specific elements of SREBP1’s mechanisms of action could be regarded as an intriguing array of targets. Particularly in melanoma, room remains to more completely characterize SREBP1’s role in oncogenic signaling for DNFA, and more fully explore its potential clinical relevance for cancer prognosis and treatment.

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds. In some embodiments, the compound is a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

where

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

each R¹ is independently optionally substituted C3-10 cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and

R² is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R³)2, wherein each R³ is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R³, together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl.

In some embodiments, the compound of formula (I) is not any one of the following compounds:

and pharmaceutically acceptable salts thereof.

In certain embodiments, n is 1 . In further embodiments, L is -CH=CH- In yet further embodiments, L is trans -CH=CH- In still further embodiments, the compound of formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.

In other embodiments, the compound of formula (I) is a compound of formula (IB):

or a pharmaceutically acceptable salt thereof.

In particular embodiments, R² is -N(R³)2. In certain embodiments, R² is a group of formula:

wherein

X is CH or N; and

R⁴ is H, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted C6-10 aryl, or optionally substituted C1 -9 heteroaryl.

In some embodiments, X is CH. In other embodiments, X is N. In further embodiments, R⁴ is optionally substituted Ce-io aryl, optionally substituted C1 -6 alkyl, or optionally substituted cycloalkyl. In yet further embodiments, R⁴ is methyl or trifluoromethyl. In still further embodiments, R⁴ is

In certain embodiments, each R³ is independently H or optionally substituted C1 -9 heterocyclyl C1-6 alkyl. In particular embodiments, R² is a group of formula:

where

one of X¹ and X² is CH2, and the remaining X¹ or X² is NR⁵ or O, wherein R⁵ is H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-io aryl, or optionally substituted Ce-io aryl C1 -6 alkyl.

In further embodiments, X¹ is CH2. In yet further embodiments, X² is CH2. In still further embodiments, the remaining X¹ or X² is O. In other embodiments, the remaining X¹ or X² is NR⁵.

In particular embodiments, R⁵ is H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkynyl, or optionally substituted Ce-io aryl C1-6 alkyl. In certain embodiments, R¹ is optionally substituted cycloalkyl, optionally substituted C1-9 heterocyclyl, or optionally substituted C2-6 alkynyloxy. In further embodiments, R¹ is optionally substituted cycloalkyl. In yet further embodiments, R¹ is optionally substituted cyclohexyl.

In still further embodiments, the compound is selected from the group consisting of: PCT/US2019/056318

pharmaceutically acceptable salts thereof

In some embodiments, the compound is a compound of formula (II):

^<RV N

\^_Z'^R3

(ii)

or a pharmaceutically acceptable salt thereof,

where

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R³ is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;

R^A is H or optionally substituted C1 -6 alkyl;

R^B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R^c is H or optionally substituted C1-6 alkyl; or R^B and R^c combine to form an optionally substituted C1 -9 heterocyclyl.

In certain embodiments, the compound of formula (II) is not a compound of any one of the following structures:

pharmaceutically acceptable salts thereof.

In particular embodiments, n is 1 . In certain embodiments, Z is -SO2-. In further embodiments, the compound of formula (II) is a compound of formula (II A) :

(I I A)

or a pharmaceutically acceptable salt thereof.

In yet further embodiments, R³ is -(CH2)-R^D, wherein R^D is optionally substituted phenyl. In still further embodiments, R^D is phenyl substituted at the para position with halogen or C1 -6 alkoxy.

In some embodiments, R¹ is -CONR^BR^c. In other embodiments, R^B is optionally substituted Ce-io aryl. In yet other embodiments, R^B is optionally substituted 6-membered heteroaryl. In still other embodiments, R^c is H.

In certain embodiments, R² is bromo. In further embodiments, R² is chloro.

In another aspect, the invention provides pharmaceutical compositions. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

where

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

each R¹ is independently optionally substituted cycloalkyl, optionally substituted C1 -6 alkyl, optionally substituted C1 -9 heterocyclyl, halogen, optionally substituted C1 -6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and

In certain embodiments, n is 1 . In particular embodiments, L is -CH=CH- (e.g., trans - CH=CH-

In particular embodiments, the compound of formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I) is a compound of formula (IB):

or a pharmaceutically acceptable salt thereof.

In further embodiments, R² is -N(R³)2. In yet further embodiments, R² is a group of formula:

wherein

X is CH or N; and

R⁴ is H, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted Ce- io aryl, or optionally substituted C1-9 heteroaryl.

In still further embodiments, X is CH. In other embodiments, X is N.

In certain embodiments, R⁴ is optionally substituted C6-10 aryl, optionally substituted C1-6 alkyl, or optionally substituted cycloalkyl. In particular embodiments, R⁴ is methyl or trifluoromethyl. In some embodiments, R⁴ is

In further embodiments, each R³ is independently H or optionally substituted C1-9 heterocyclyl C1 -6 alkyl. In yet further embodiments, R² is a group of formula:

wherein

one of X¹ and X² is CH2, and the remaining X¹ or X² is NR⁵ or O, wherein R⁵ is H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-io aryl, or optionally substituted Ce-io aryl C1 -6 alkyl. In still further embodiments, X¹ is CH2. In other embodiments, X² is CH2. In yet other embodiments, the remaining X¹ or X² is O. In still other embodiments, the remaining X¹ or X² is NR⁵.

In some embodiments, R⁵ is H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkynyl, or optionally substituted Ce-io aryl C1 -6 alkyl. In certain embodiments, R¹ is optionally substituted cycloalkyl, optionally substituted C1-9 heterocyclyl, or optionally substituted C2-6 alkynyloxy. In particular embodiments, R¹ is optionally substituted cycloalkyl. In further embodiments, R¹ is optionally substituted cyclohexyl. In yet further embodiments, the compound is a compound of any aspect.

In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a compound of formula (II) :

or a pharmaceutically acceptable salt thereof,

where

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1 -6 alkyl;

R^A is H or optionally substituted C1 -6 alkyl; and

In certain embodiments, n is 1 . In particular embodiments, Z is -SO2-. In further embodiments, the compound of formula (II) is a compound of formula (II A) :

(I I A)

or a pharmaceutically acceptable salt thereof.

In other embodiments, R¹ is -CONR^BR^c. In yet other embodiments, R^B is optionally substituted C6-10 aryl. In still other embodiments, R^B is optionally substituted 6-membered heteroaryl. In further embodiments, R^c is H. In yet further embodiments, R² is halogen (e.g., R² is chloro). In still further embodiments, the compound is a compound of any aspect. In yet another aspect, the invention provides a method of treating cancer in a subject by administering to the subject in need thereof a therapeutically effective amount of the compound of the invention or the pharmaceutical composition of the invention.

In some embodiments, the compound is a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

where

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

In certain embodiments, the compound is a compound of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1 -6 alkyl; and

In particular embodiments, the cancer is melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer (e.g., clear cell renal cell carcinoma). In further embodiments, the cancer is metastatic. In still another aspect, the invention provides a method of treating a metabolic disorder in a subject by administering to the subject in need thereof a therapeutically effective amount of the compound of the invention or the pharmaceutical composition of the invention.

In some embodiments the compound is a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

where

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

In certain embodiments, the compound is a compound of formula (II):

or a pharmaceutically acceptable salt thereof,

where

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1 -6 alkyl; and

In further embodiments, the metabolic disorder is nonalcoholic steatohepatitis or cardiovascular disease. In a further aspect, the invention provides a method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP in a subject in need thereof by administering to the subject an effective amount of the compound of the invention or the pharmaceutical composition of the invention.

In some embodiments, the compound is a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

where

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

In certain embodiments, the compound is a compound of formula (II):

or a pharmaceutically acceptable salt thereof,

where

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1 -6 alkyl; and

In further embodiments of any aspect, the compound or the pharmaceutical composition is administered enterally (e.g., orally). In yet further embodiments, the compound or the pharmaceutical composition is administered parenterally (e.g., intramuscularly, intratumorally, intravenously, subcutaneously, buccally, sublingually, sublabially, by inhalation, intra-arterially, intraventricularly, intraspinally, intrathecally, intraorbitally, intracranially, or topically).

In still further embodiments, the subject is a human.

In some embodiments, the method further includes administering a fatty acid/cholesterol homeostatsis modulator. In certain embodiments, the method further includes administering an inducer of ferroptotic cell death. In particular embodiments, the method further includes administering 666-1 5, fatostatin, A-485, PF429242, erastin, or a pharmaceutically acceptable salt thereof.

In a yet further aspect, the invention provides a method of killing a cancer cell by contacting the cancer cell with the compound of the invention.

In some embodiments, the compound is a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

In certain embodiments, the compound is a compound of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1 -6 alkyl; and

In further embodiments, the cancer cell is a melanoma cell, glioblastoma cell, prostate cancer cell, non-small cell lung cancer cell, or kidney cancer cell. In yet further embodiments, the cell is in a subject. In still further embodiments, the subject is human. In some embodiments, the method further includes contacting the cancer cell with a fatty acid/cholesterol homeostatsis modulator. In certain embodiments, the method further includes contacting the cancer cell with an inducer of ferroptotic cell death. In particular embodiments, the method further includes contacting the cancer cell with 666-15, fatostatin, A-485, PF429242, or erastin.

In yet another aspect, the invention provides an agent capable of binding the KIX domain of CBP or MED15 to inhibit the binding between SREBP1 and the KIX domain of MED15 or CBP. In some embodiments, the agent is not a compound of any one of the following structures:

pharmaceutically acceptable salts thereof.

In certain embodiments, the agent is a small molecule (e.g., the small molecule is a compound of the invention). In particular embodiments, the agent is an antigen-binding protein (e.g., an antibody or an antigen-binding fragment thereof).

In a further aspect, the invention provides a method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP by contacting MED15 or CBP with the agent of the invention.

In some embodiments, MED15 is in a cell. In certain embodiments, CBP is in a cell. In further embodiments, the cell is in a subject in need of inhibition of the binding between SREBP1 and the KIX domain of MED15 or CBP. In yet further embodiments, the subject suffers from a cancer. In still further embodiments, the cancer is melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer. In other embodiments, the subject suffers from a metabolic disorder.

In yet other embodiments, the metabolic disorder is nonalcoholic steatohepatitis or a cardiovascular disease. The present disclosure also includes the following enumerated items

A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

R² is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R³)2, wherein each R³ is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R³, together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl;

provided that the compound is not any one of the following compounds:

and pharmaceutically acceptable salts thereof.

2. The compound of item 1 , wherein n is 1 .

3. The compound of item 1 or 2, wherein L is -CH=CH-

4. The compound of any one of items 1 to 3, wherein L is trans -CH=CH- 5. The compound of item 1 , wherein the compound is of formula (IA):

or a pharmaceutically acceptable salt thereof.

6. The compound of item 1 , wherein the compound is of formula (IB):

or a pharmaceutically acceptable salt thereof.

7. The compound of any one of items 1 to 6, wherein R² is -N(R³)2.

8. The compound of any one of items 1 to 7, wherein R² is a group of formula:

wherein

X is CH or N; and

9. The compound of item 8, wherein X is CH.

10. The compound of item 8, wherein X is N.

1 1 . The compound of any one of items 8 to 10, wherein R⁴ is optionally substituted C6-10 aryl, optionally substituted C1 -6 alkyl, or optionally substituted cycloalkyl.

12. The compound of any one of items 8 to 10, wherein R⁴ is methyl or trifluoromethyl.

13. The compound of any one of items 8 to 10, wherein R⁴ is

14. The compound of any one of items 1 to 7, wherein each R³ is independently H or optionally substituted C1-9 heterocyclyl C1-6 alkyl.

15. The compound of item 14, wherein R² is a group of formula:

wherein

16. The compound of item 15, wherein X¹ is CH2.

17. The compound of item 15, wherein X² is CH2.

18. The compound of any one of items 15 to 17, wherein the remaining X¹ or X² is O.

19. The compound of any one of items 15 to 17, wherein the remaining X¹ or X² is NR⁵.

20. The compound of item 19, wherein R⁵ is H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkynyl, or optionally substituted Ce-io aryl C1-6 alkyl.

21. The compound of any one of items 1 to 20, wherein R¹ is optionally substituted cycloalkyl, optionally substituted C1 -9 heterocyclyl, or optionally substituted C2-6 alkynyloxy.

22. The compound of item 21 , wherein R¹ is optionally substituted cycloalkyl.

23. The compound of item 21 , wherein R¹ is optionally substituted cyclohexyl.

24. A compound selected from the group consisting of:

pharmaceutically acceptable salts thereof. 25. A compound of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R³ is optionally substituted Ob-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;

R^A is H or optionally substituted C1-6 alkyl;

R^B is optionally substituted Ob-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1-9 heterocyclyl C1-6 alkyl; and R^c is H or optionally substituted C1-6 alkyl; or R^B and R^c combine to form an optionally substituted C1-9 heterocyclyl ;

provided that the compound is not a compound of any one of the following structures:

pharmaceutically acceptable salts thereof.

26. The compound of item 25, wherein n is 1 .

27. The compound of item 25 or 26, wherein Z is -SO2-.

28. The compound of item 25, wherein the compound is of formula (IIA):

or a pharmaceutically acceptable salt thereof. 29. The compound of any one of items 25 to 28, wherein R³ is -(CH2)-R^D, wherein R^D is optionally substituted phenyl.

30. The compound of item 28, wherein R^D is phenyl substituted at the para position with halogen or C1-6 alkoxy.

31 . The compound of any one of items 25 to 29, wherein R¹ is -CONR^BR^c.

32. The compound of any one of items 25 to 30, wherein R^B is optionally substituted Ce-io aryl.

33. The compound of any one of items 25 to 30, wherein R^B is optionally substituted 6-membered heteroaryl.

34. The compound of any one of items 25 to 32, wherein R^c is H.

35. The compound of any one of items 25 to 34, wherein R² is bromo.

36. The compound any one of items 25 to 34, wherein R² is chloro.

37. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

38. The pharmaceutical composition of item 37, wherein n is 1 .

39. The pharmaceutical composition of item 37 or 38, wherein L is -CH=CH- 40. The pharmaceutical composition of any one of items 37 to 39, wherein L is trans -CH=CH-

41 . The pharmaceutical composition of item 37, wherein the compound is of formula (IA):

or a pharmaceutically acceptable salt thereof.

42. The pharmaceutical composition of item 37, wherein the compound is of formula (IB):

or a pharmaceutically acceptable salt thereof.

43. The pharmaceutical composition of any one of items 37 to 42, wherein R² is -N(R³)2.

44. The pharmaceutical composition of any one of items 37 to 42, wherein R² is a group of formula:

wherein

X is CH or N; and

45. The pharmaceutical composition of item 44, wherein X is CH.

46. The pharmaceutical composition of item 44, wherein X is N.

47. The pharmaceutical composition of any one of items 44 to 46, wherein R⁴ is optionally substituted

C6-10 aryl, optionally substituted C1 -6 alkyl, or optionally substituted cycloalkyl.

48. The pharmaceutical composition of any one of items 44 to 46, wherein R⁴ is methyl or trifluoromethyl.

49. The pharmaceutical composition of any one of items 44 to 46, wherein R⁴ is

50. The pharmaceutical composition of any one of items 37 to 43, wherein each R³ is independently H or optionally substituted C1-9 heterocyclyl C1-6 alkyl.

51 . The pharmaceutical composition of item 50, wherein R² is a group of formula:

wherein

52. The pharmaceutical composition of item 51 , wherein X¹ is CH2.

53. The pharmaceutical composition of item 51 , wherein X² is CH2.

54. The pharmaceutical composition of any one of items 51 to 53, wherein the remaining X¹ or X² is O.

55. The pharmaceutical composition of any one of items 51 to 54, wherein the remaining X¹ or X² is NR⁵.

56. The pharmaceutical composition of item 55, wherein R⁵ is H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, or optionally substituted Ce-io aryl C1 -6 alkyl.

57. The pharmaceutical composition of any one of items 37 to 56, wherein R¹ is optionally substituted cycloalkyl, optionally substituted C1-9 heterocyclyl, or optionally substituted C2-6 alkynyloxy.

58. The pharmaceutical composition of item 57, wherein R¹ is optionally substituted cycloalkyl.

59. The pharmaceutical composition of item 57, wherein R¹ is optionally substituted cyclohexyl.

60. The pharmaceutical composition of item 37, wherein the compound is a compound of any one of items 1 to 24.

61 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1 -6 alkyl;

R^A is H or optionally substituted C1 -6 alkyl; and

62. The pharmaceutical composition of item 61 , wherein n is 1 .

63. The pharmaceutical composition of item 61 or 62, wherein Z is -SO2-.

64. The pharmaceutical composition of item 61 , wherein the compound is of formula (IIA):

or a pharmaceutically acceptable salt thereof.

65. The pharmaceutical composition of any one of items 61 to 64, wherein R³ is -(CH2)-R^D, wherein R^D is optionally substituted phenyl.

66. The pharmaceutical composition of item 65, wherein R^D is phenyl substituted at the para position with halogen or C1-6 alkoxy.

67. The pharmaceutical composition of any one of items 61 to 66, wherein R¹ is -CONR^BR^c.

68. The pharmaceutical composition of any one of items 61 to 67, wherein R^B is optionally substituted C6-10 aryl. 69. The pharmaceutical composition of any one of items 61 to 67, wherein R^B is optionally substituted 6-membered heteroaryl.

70. The pharmaceutical composition of any one of items 61 to 69, wherein R^c is H.

71 . The pharmaceutical composition of any one of items 61 to 70, wherein R² is halogen.

72. The pharmaceutical composition of any one of items 61 to 71 , wherein the compound is a compound of any one of items 25 to 36.

73. A method of treating cancer in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of items 1 to 36, the pharmaceutical composition of any one of items 37 to 72, the compound of formula (I), or the compound of formula (II); wherein the compound of formula (I) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

R² is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R³)2, wherein each R³ is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1 -6 alkyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl, or both R³, together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl; and

wherein the compound of formula (II) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen; R³ is optionally substituted Ce-io aryl C1 -6 alkyl or optionally substituted C1 -6 alkyl;

R^A is H or optionally substituted C1 -6 alkyl; and

74. The method of item 73, wherein the cancer is melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer.

75. The method of item 73 or 74, wherein the cancer is metastatic.

76. A method of treating a metabolic disorder in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of items 1 to 36, the pharmaceutical composition of any one of items 37 to 72, a compound of formula (I), or a compound of formula (II);

wherein the compound of formula (I) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

wherein the compound of formula (II) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2; Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1 -6 alkyl; and

77. The method of item 76, wherein the metabolic disorder is nonalcoholic steatohepatitis or cardiovascular disease.

78. A method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of items 1 to 36, the pharmaceutical composition of any one of items 37 to 72, a compound of formula (I), or a compound of formula (II);

wherein the compound of formula (I) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

wherein the compound of formula (II) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1 -6 alkyl; and

79. The method of any one of items 73 to 78, wherein the compound or the pharmaceutical composition is administered enterally.

80. The method of item 79, wherein the compound or the pharmaceutical composition is

administered orally.

81 . The method of any one of items 73 to 80, wherein the compound or the pharmaceutical composition is administered parenterally.

82. The method of item 81 , wherein the compound or the pharmaceutical composition is

administered intramuscularly, intratumorally, intravenously, subcutaneously, buccally, sublingually, sublabially, by inhalation, intra-arterially, intraventricularly, intraspinally, intrathecally, intraorbitally, intracranially, or topically.

83. The method of any one of items 73 to 82, wherein the subject is a human.

84. The method of any one of items 73 to 83, wherein the method further comprises administering a fatty acid/cholesterol homeostatsis modulator.

85. The method of any one of items 73 to 83, wherein the method further comprises administering an inducer of ferroptotic cell death.

86. The method of any one of items 73 to 83, wherein the method further comprises administering 666-1 5, fatostatin, A-485, PF429242, erastin, or a pharmaceutically acceptable salt thereof.

87. A method of killing a cancer cell comprising contacting the cancer cell with the compound of any one of items 1 to 36, a compound of formula (I), or a compound of formula (II);

wherein the compound of formula (I) has the following structure:

(I)

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

wherein the compound of formula (II) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1 -6 alkyl; and

88. The method of item 87, wherein cancer cell is a melanoma cell, glioblastoma cell, prostate cancer cell, non-small cell lung cancer cell, or kidney cancer cell.

89. The method of item 87 or 88, wherein the cell is in a subject.

90. The method of item 89, wherein the subject is human.

91 . The method of any one of items 87 to 90, wherein the method further comprises contacting the cancer cell with a fatty acid/cholesterol homeostatsis modulator. 92. The method of any one of items 87 to 90, wherein the method further comprises contacting the cancer cell with an inducer of ferroptotic cell death.

93. The method of any one of items 87 to 90, wherein the method further comprises contacting the cancer cell with 666-15, fatostatin, A-485, PF429242, or erastin.

94. An agent capable of binding the KIX domain of CBP or MED1 5 to inhibit the binding between SREBP1 and the KIX domain of MED1 5 or CBP, wherein the agent is not a compound of any one of the following structures:

pharmaceutically acceptable salts thereof.

95. The agent of item 94, wherein the agent is a small molecule.

96. The agent of item 95, wherein the agent is the compound of any one of items 1 to 36.

97. The agent of item 94, wherein the agent is an antigen-binding protein.

98. The agent of item 97, wherein the antigen-binding protein is an antibody or an antigen-binding fragment thereof.

99. A method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP, the method comprising contacting MED1 5 or CBP with the agent of any one of items 94 to 98.

100. The method of item 99, wherein MED15 or CBP is in a cell. 101 . The method of item 100, wherein the cell is in a subject in need of inhibition of the binding between SREBP1 and the KIX domain of MED15 or CBP.

102. The method of item 101 , wherein the subject suffers from a cancer.

103. The method of item 102, wherein the cancer is melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer.

104. The method of item 101 , wherein the subject suffers from a metabolic disorder.

105. The method of item 104, wherein the metabolic disorder is nonalcoholic steatohepatitis or a cardiovascular disease.

Definitions

The term“about,” as used herein, represents a value that is in the range of ±10% of the value that follows the term“about.”

The term“acyl,” as used herein, represents a monovalent substituent -C(0)-R, where R is alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, or heterocyclyl.

The term“acyloxy,” as used herein, represents a monovalent substituent -OR, where R is acyl. The term“alkenyl,” as used herein, represents an acyclic, straight or branched chain, monovalent hydrocarbon group containing one, two, or three carbon-carbon double bonds. Unless otherwise specified, an unsubstituted alkenyl has a carbon count from two to six. Non-limiting examples of the alkenyl groups include ethenyl, prop-1 -enyl, prop-2-enyl, 1 -methylethenyl, but-1 -enyl, but-2-enyl, but-3- enyl, 1 -methylprop-1 -enyl, 2-methylprop-1 -enyl, 1 -methylprop-2-enyl, and the like. An optionally substituted alkenyl is an alkenyl group that is optionally substituted as described herein for alkyl.

The term“alkenyloxy,” as used herein, represents a chemical substituent of formula -OR, where R is a C2-6 alkenyl group, unless otherwise specified. An optionally substituted alkenyloxy is an alkenyloxy group that is optionally substituted as described herein for alkyl.

The term“alkoxy,” as used herein, represents a chemical substituent of formula -OR, where R is a C1 -6 alkyl group, unless otherwise specified. An optionally substituted alkoxy is an alkoxy group that is optionally substituted as described herein for alkyl.

The term“alkoxyaryl,” as used herein, represents an aryl substituted with 1 , 2, or 3 groups independently selected from alkoxy.

The term“alkyl,” as used herein, represents an acyclic, straight or branched chain, saturated hydrocarbon group, which, when unsubstituted, has from one to six carbon atoms, unless otherwise specified. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, neopentyl, and the like. Alkyl may be optionally substituted, valency permitting, with one, two, three, four, or five unsubstituted substituents independently selected from the group consisting of: alkoxy; acyloxy; aryloxy; arylalkoxy; cycloalkyl; cycloalkoxy; halogen; heterocyclyl;

heteroaryl; heterocyclyloxy; heteroaryloxy; hydroxyl; nitro; thiol; =0; =S; -NR2, where each R is independently hydrogen, alkyl, acyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl. The term“alkynyl,” as used herein, represents an acyclic, straight or branched chain, monovalent hydrocarbon group of from two to six carbon atoms containing one or two carbon-carbon triple bond. Non-limiting examples of alkynyl groups include ethynyl, 1 -propynyl, 2-propynyl, 2-butynyl, and the like.

An optionally substituted alkynyl is an alkynyl that is optionally substituted as described herein for alkyl.

The term“alkynyloxy,” as used herein, represents a chemical substituent of formula -OR, where R is a C2-6 alkynyl group, unless otherwise specified. An optionally substituted alkynyloxy is an alkynyloxy group that is optionally substituted as described herein for alkyl.

The term“amino,” as used herein, represents a monovalent substituent -NH2 or a divalent substituent -NH-.

The term“antibody,” as used herein, refers to at least the variable domain of a heavy chain, and normally comprises at least the variable domains of a heavy chain and of a light chain of an

immunoglobulin, which bind to an antigen of interest. Antibodies and antigen-binding fragments include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab' and F(ab')2, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv), fragments comprising either a VL or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-ld) antibodies. Antibody molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG 1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass of immunoglobulin molecule.

The term“aryl,” as used herein, represents a monocyclic, bicyclic, or tricyclic carbocyclic ring system having one or two aromatic rings. Unless otherwise specified, unsubstituted aryl groups have a carbon count of six to fourteen (preferably, six to ten). All atoms within an unsubstituted carbocyclic aryl group are carbon atoms. Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1 ,2- dihydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, etc. Unless otherwise specified, aryl may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; acyl; acyloxy; alkenyl; alkynyl; alkoxy; aryl; aryloxy; aryloyl; arylalkyl; arylalkoxy; cycloalkyl; cycloalkoxy; halogen; haloalkyl; haloalkoxy; heterocyclyl; heteroaryl;

heterocyclyloxy; heteroaryloxy; hydroxyl; nitro; thiol; cyano; -NR2, where each R is independently hydrogen, alkyl, acyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; -SR^A; -COOR^A, where R^A is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; -CON(R^B)2; and -S02N(R^B)2, where each R^B is independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl.

The term“aryl alkenyl,” as used herein, represents an alkenyl group substituted with one or two aryl group(s). In optionally substituted aryl alkenyl, each of the aryl and alkenyl portions may be independently, optionally substituted as described herein for aryl and alkyl, respectively.

The term“aryl alkyl,” as used herein, represents an alkyl group substituted with one or two aryl group(s). In optionally substituted aryl alkyl, each of the aryl and alkyl portions may be independently, optionally substituted as described herein for aryl and alkyl, respectively.

The term“arylalkoxy,” as used herein, represents a substituent of formula -OR, where R is arylalkyl. In optionally substituted aryl alkoxy, the arylalkyl is optionally substituted as described herein for aryl alkyl.

The term“aryloxy,” as used herein, represents a chemical substituent of formula -OR, where R is aryl. In optionally substituted aryloxy, the aryl group is optionally substituted as described herein for aryl.

The term“carbonyl,” as used herein, represents a -C(O)- group. The term“CBP,” as used herein, represents a CREB-binding protein (e.g., a human CREB- binding protein) having a KIX domain. Exemplary CBP protein sequences are given by NCBI Reference Sequences: NP_004371 .2 (isoform a) and NP 001073315.1 (isoform b).

The expression“Cx-y,” as used herein, indicates that the group, the name of which immediately follows the expression, when unsubstituted, contains a total of from x to y carbon atoms. If the group is a composite group (e.g., aryl alkyl), Cx-_y indicates that the portion, the name of which immediately follows the expression, when unsubstituted, contains a total of from x to y carbon atoms. For example, (Ce-io- aryl)-Ci-6-alkyl is a group, in which the aryl portion, when unsubstituted, contains a total of from 6 to 10 carbon atoms, and the alkyl portion, when unsubstituted, contains a total of from 1 to 6 carbon atoms.

The term“cycloalkyl,” as used herein, represents a monovalent, cyclic, non-aromatic, hydrocarbon group having from three to ten carbons, unless otherwise specified. Cycloalkyl groups may be monocyclic, bicyclic, spirocyclic, or caged (e.g., adamantyl). Fused bicyclic cycloalkyl groups may be of bicyclo[p.q.0]alkyl type, in which each of p and q is, independently, 1 , 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 2, 3, 4, 5, 6, 7, or 8. Alternatively, fused bicyclic cycloalkyl groups may include bridged cycloalkyl structures, e.g., bicyclo[p.q.r]alkyl, in which r is 1 , 2, or 3, each of p and q is, independently, 1 , 2, 3, 4, 5, or 6, provided that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. The spirocyclic cycloalkyl group may be spiro[p.q]alkyl, in which each of p and q is, independently, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 4, 5, 6, 7, 8, or 9. Cycloalkyl may be saturated or unsaturated. An unsaturated cycloalkyl contains one or two carbon-carbon double bonds. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex-1 -enyl, cyclohex-2-enyl, cyclohex-3-enyl, cycloheptyl, 1 -bicyclo[2.2.1 ]heptyl, 2-bicyclo[2.2.1 ]heptyl, 5-bicyclo[2.2.1 ]heptyl, 7- bicyclo[2.2.1 ]heptyl, and decalinyl. The cycloalkyl group may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkoxy; acyloxy; aryloxy; arylalkoxy; cycloalkyl; cycloalkoxy; halogen; haloalkyl; haloalkoxy; heterocyclyl; heteroaryl;

heterocyclyloxy; heteroaryloxy; hydroxyl; nitro; thiol; =0; =S; -NR2, where each R is independently hydrogen, alkyl, acyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; -COOR^A, where R^A is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; and -CON(R^B)2, where each R^B is independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl.

The term“cycloalkoxy,” as used herein, represents a group -OR, where R is cycloalkyl.

The term“haloalkyl,” as used herein, represents an alkyl substituted with one or more halogens (e.g., fluorine) as described herein. Non-limiting examples of haloalkyl include trifluoromethyl, 2,2,2- trifluoroethyl, and pentafluoroethyl.

The term“haloalkoxy,” as used herein, represents a substituent -OR, where R is haloalkyl.

The term“haloaryl,” as used herein, represents an aryl substituted with 1 , 2, or 3 groups independently selected from halogens.

The term“halogen,” as used herein, represents bromine, chlorine, iodine, or fluorine.

The term“heteroaryl,” as used herein, represents a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridging 5-, 6-, 7-, or 8-membered rings, the ring system containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; where at least one of the rings is an aromatic ring. Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl (e.g., 1 ,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, etc. The term bicyclic, tricyclic, and tetracyclic heteroaryls include at least one ring having at least one heteroatom as described above and at least one aromatic ring; the at least one heteroatom may be present in the at least one aromatic ring. For example, a ring having at least one heteroatom may be fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring. Examples of fused heteroaryls include 1 ,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3- dihydrobenzothiophene. Heteroaryl may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of: alkyl; alkoxy; acyloxy; aryloxy; aryloyl; arylalkyl; arylalkoxy; cycloalkyl; cycloalkoxy; halogen; haloalkyl; haloalkoxy; heterocyclyl; heteroaryl; heterocyclyloxy; heteroaryloxy; hydroxyl; nitro; thiol; cyano; =0; -NR2, where each R is independently hydrogen, alkyl, acyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; -SR^A; -COOR^A, where R^A is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; -SC>2N(R^B)2; and -CON(R^B)2, where each R^B is independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl.

The term“heteroaryloxy,” as used herein, represents a group -OR, where R is heteroaryl.

The term“heterocyclyl,” as used herein, represents a monocyclic, bicyclic, tricyclic, or tetracyclic non-aromatic ring system having fused or bridging 4-, 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, the ring system containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Non-aromatic 5-membered heterocyclyl has zero or one double bonds, non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds, and non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and/or zero or one carbon- carbon triple bond. Heterocyclyl groups have a carbon count of 1 to 16 carbon atoms unless otherwise specified. Certain heterocyclyl groups may have a carbon count up to 9 carbon atoms. Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl,

tetrahydrothienyl, dihydrothienyl, pyranyl, dihydropyranyl, dithiazolyl, benzodioxolyl, etc. The term “heterocyclyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., quinuclidine, tropanes, or diaza-bicyclo[2.2.2]octane. The term“heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another heterocyclic ring. Examples of fused heterocyclyls include 1 ,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene. The heterocyclyl group may be unsubstituted or substituted with one, two, three, four or five substituents independently selected from the group consisting of: alkyl; alkoxy; acyloxy; aryl; aryl alkyl; aryloxy; aryloyl; arylalkyl; arylalkoxy;

cycloalkyl; cycloalkoxy; halogen; haloalkyl; haloalkoxy; heterocyclyl; heteroaryl; heterocyclyloxy;

heteroaryloxy; hydroxyl; nitro; thiol; cyano; =0; =S; -NR2, where each R is independently hydrogen, alkyl, acyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; -SR^A; -COOR^A, where R^A is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; -SC>2N(R^B)2; and -CON(R^B)2, where each R^B is independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl. Any of the optional substituents described for heterocyclyl may be further optionally substituted with unsubstituted substituent(s) as described herein for each respective substituent. For example, a C1-9 heterocyclyl may be optionally substituted with alkoxyaryl or haloaryl.

The term“heterocyclyl alkyl,” as used herein, represents an alkyl group substituted with one or two heterocyclyl group(s). In optionally substituted heterocyclyl alkyl, each of the heterocyclyl and alkyl portions may be independently, optionally substituted as described herein for heterocyclyl and alkyl, respectively.

The term“heterocyclyloxy,” as used herein, represents a group -OR, where R is heterocyclyl.

The terms“hydroxyl” and“hydroxy,” as used interchangeably herein, represent -OH.

The term“inhibit,” as used herein, refers to a reduction in the binding between a target protein and another protein by a compound at an IC50 sufficient to elicit a desired phenotypic response (e.g., cell death) in a cell (e.g., at an IC50 of 1 mM or less (e.g., 500 mM or less, 300 mM or less, 200 mM or less,

100 mM or less, 50 mM or less, or 10 mM or less)).

The term“MED15,” as used herein, represents a mediator of RNA polymerase II transcription subunit 15 protein (e.g., a human mediator of RNA polymerase II transcription subunit 15 protein) having a KIX domain. Exemplary MED15 protein sequences are given by NCBI Reference Sequences:

NP_001 003891 .1 (isoform a), NP_056973.2 (isoform b), NP_001280163.1 (isoform c), NP_001280164.1 (isoform d), and NP 001280165.1 (isoform e).

The term“oxo,” as used herein, represents a divalent oxygen atom (e.g., the structure of oxo may be shown as =0).

The term“pharmaceutically acceptable,” as used herein, refers to those compounds, materials, compositions, and/or dosage forms, which are suitable for contact with the tissues of an individual (e.g., a human), without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.

The term“pharmaceutically acceptable salt,” as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al. , J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate,

benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

The term“protecting group,” as used herein, represents a group intended to protect a hydroxy, an amino, or a carbonyl from participating in one or more undesirable reactions during chemical synthesis. The term“O-protecting group,” as used herein, represents a group intended to protect a hydroxy or carbonyl group from participating in one or more undesirable reactions during chemical synthesis. The term“/V-protecting group,” as used herein, represents a group intended to protect a nitrogen containing (e.g., an amino or hydrazine) group from participating in one or more undesirable reactions during chemical synthesis. Commonly used O- and /V-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” 3^rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Exemplary O- and /V-protecting groups include alkanoyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, f-butyldimethylsilyl, tri-/^'so-propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4- isopropylpehenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl.

Exemplary O-protecting groups for protecting carbonyl containing groups include, but are not limited to: acetals, acylals, 1 ,3-dithianes, 1 ,3-dioxanes, 1 ,3-dioxolanes, and 1 ,3-dithiolanes.

Other O-protecting groups include, but are not limited to: substituted alkyl, aryl, and aryl-alkyl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2,- trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1 -[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p- methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl;

dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and

diphenymethylsilyl); carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2- trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl).

Other /V-protecting groups include, but are not limited to, chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl- containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,

3.4.5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methylethoxycarbonyl, a,a-dimethyl-

3.5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl,

diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, aryl-alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like and silyl groups such as trimethylsilyl, and the like. Useful /V-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). The term“SREBP,” as used herein, represents a Sterol Regulatory Element-binding Protein 1 (e.g., a human Sterol Regulatory Element-binding Protein). Exemplary SREBP sequences are given by NCBI Reference Sequences: NP 001005291 .1 (isoform a), NP_004167.3 (isoform b), and

NR 001308025.1 (isoform c). Preferably, SREBP is SREBP isoform a.

The term“subject,” as used herein, represents a human or non-human animal (e.g., a mammal) that is suffering from, or is at risk of, a disease or condition, as determined by a qualified professional (e.g., a doctor or a nurse practitioner) with or without known in the art laboratory test(s) of sample(s) from the patient.

“Treatment” and "treating," as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent or cure a disease or condition. This term includes active treatment (treatment directed to improve the disease or condition); causal treatment (treatment directed to the cause of the associated disease or condition); palliative treatment (treatment designed for the relief of symptoms of the disease or condition); preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease or condition); and supportive treatment (treatment employed to supplement another therapy).

The compounds described herein, unless otherwise noted, encompass isotopically enriched compounds (e.g., deuterated compounds), tautomers, and all stereoisomers and conformers (e.g.

enantiomers, diastereomers, E/Z isomers, atropisomers, etc.), as well as racemates thereof and mixtures of different proportions of enantiomers or diastereomers, or mixtures of any of the foregoing forms as well as salts (e.g., pharmaceutically acceptable salts).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 A is a chart showing the ATP production normalized to the DMSO control being a proxy for the cell viability as a function of the compound concentration.

FIG. 1 B is a chart showing the ATP production normalized to the DMSO control being a proxy for the cell viability as a function of the compound concentration.

FIG. 2A is a chart showing the approximate concentrations of SCD1 , HMGCR, and FASN transcripts normalized to the DMSO control as a function of the compound concentration.

FIG. 2B is a chart showing the approximate concentrations of SCD1 , HMGCR, and FASN transcripts normalized to the DMSO control as a function of the compound concentration.

FIG. 3A is a graph showing normalized luciferase reading observed for X1 in a FASN-luciferase assay.

FIG. 3B is a graph showing P32 dose-dependent reduction in the normalized luciferase readings.

FIG. 4A is a graph showing Cell Titer-Glo (CTG) signal level normalized to a vehicle control in response to P32, P28, or P22.

FIG. 4B is a graph showing the fold-change in the transcript abundance in cells incubated with a vehicle, P32, P28, or P22. The data are normalized to the transcript abundance in cells incubated with a vehicle.

FIG. 5A is a graph showing Cell Titer-Glo signal level normalized to a vehicle control in response to X1 , A30, and A7. FIG. 5B is a graph showing the fold-change in the transcript abundance in cells incubated with a vehicle, X1 , A30, and A7. The data are normalized to the transcript abundance in cells incubated with a vehicle.

FIG. 6A is a Kaplan-Meier survival plot for mice implanted with MGG8 cells and treated with DMSO (control), P32, or X1 .

FIG. 6B is a Kaplan-Meier survival plot for mice implanted with U251 -MG cells and treated with DMSO (control) or A1 .

FIG. 7 is a chart showing cell viability assay results for P32 and X1 . Glioblastomas (GBMs) carrying EGFR activating mutations have increased SREBP activity and activation of lipogenic gene expression. Inhibition of SREBP is shown to induce GBM cell death.

FIG. 8A is a chart assessing ATP product and caspase 3/7 levels in cells transfected with siRNA targeting SREBF1 , SREBF2, or both SREBF1 and SREBF2 relative to non-transfected cells (NT).

FIG. 8B is a chart showing SREBF1 and SREBF2 transcript abundance in cells transfected with siRNA targeting SREBF1 , SREBF2, or both SREBF1 and SREBF2. The data are normalized to the RPLP0 transcript levels.

FIG. 8C is a chart showing SCD1 , FASN, and HMGCR transcript abundance in cells transfected with siRNA targeting SREBF1 , SREBF2, or both SREBF1 and SREBF2. The data are normalized to the RPLP0 transcript levels.

FIG. 9A is a chart showing the SCD1 , HMGCR, FASN, ACC, and SREBF1 transcript abundance in cells treated with DMSO or P32. The data are normalized to the b-actin levels and the DMSO control.

FIG. 9B is a chart showing the SCD1 , HMGCR, FASN, ACC, and SREBF1 transcript abundance in cells treated with DMSO or P1 . The data are normalized to the b-actin levels and the DMSO control.

FIG. 10A is a chart showing the SCD1 , HMGCR, FASN, ACC, and SREBF1 transcript abundance in cells treated with DMSO or X1 . The data are normalized to the b-actin levels and the DMSO control.

FIG. 10B is a chart showing the SCD1 , HMGCR, FASN, ACC, and SREBF1 transcript abundance in cells treated with DMSO or A1 . The data are normalized to the b-actin levels and the DMSO control.

FIG. 1 1 A is a chart showing CTG signal curves for A1 , X1 , and P32 in 10% FBS. The signal is normalized to DMSO.

FIG. 1 1 B is a chart showing CTG signal curves for A1 , X1 , and P32 in 1 % LDPS. The signal is normalized to DMSO.

FIG. 12 is a chart showing CTG signal levels observed in cancer cells treated with X1 .

FIG. 13 is a chart showing changes in the SCD1 , FASN, and HMGCR transcript abundance in cells treated with P32. The data are normalized to the b-actin levels and the vehicle control.

FIG. 14 is a chart showing changes in the SCD1 , FASN, and HMGCR transcript abundance in cells treated with X1 . The data are normalized to the b-actin levels and the vehicle control.

FIG. 15A is a chart showing dose dependent CTG and caspase glo responses to P32. The Y- axis on the right corresponds to the CTG response normalized to the DMSO control, and the Y-axis on the left corresponds to the caspase glo response normalized to the DMSO control.

FIG. 15B is a chart showing dose dependent CTG and caspase glo signals to X1 . The Y-axis on the right corresponds to the CTG signal normalized to the DMSO control, and the Y-axis on the left corresponds to the caspase glo signal normalized to the DMSO control. FIG. 16A is a chart showing dose dependent, normalized CTG signal levels in RCC-AB cells treated with varying concentrations of erastin and P32. The data are normalized to DMSO. The X-axis shows P32 concentrations (mM).

FIG. 16B is a chart showing Bliss synergy scores for P32/erastin combination therapy in RCC-AB cells. The max score was 15.53.

FIG. 17A is a chart showing dose dependent, normalized CTG signal levels in RCC-FG2 cells treated with varying concentrations of erastin and P32. The data are normalized to DMSO. The X-axis shows P32 concentrations (pM).

FIG. 17B is a chart showing Bliss synergy scores for P32/erastin combination therapy in RCC- FG2 cells. The max score was 22.09.

FIG. 18A is a chart showing dose dependent, normalized CTG signal levels in RCC-JF cells treated with varying concentrations of erastin and P32. The data are normalized to DMSO. The X-axis shows P32 concentrations (pM).

FIG. 18B is a chart showing Bliss synergy scores for P32/erastin combination therapy in RCC-JF cells. The max score was 37.2.

FIG. 19A is a chart showing dose dependent, normalized CTG signal levels in RCC-AB cells treated with varying concentrations of erastin and X1 . The data are normalized to DMSO. The X-axis shows X1 concentrations (pM).

FIG. 19B is a chart showing Bliss synergy scores for X1 /erastin combination therapy in RCC-AB cells. The max score was -2.24.

FIG. 20A is a chart showing dose dependent, normalized CTG signal levels in RCC-FG2 cells treated with varying concentrations of erastin and X1 . The data are normalized to DMSO. The X-axis shows X1 concentrations (pM).

FIG. 20B is a chart showing Bliss synergy scores for X1 /erastin combination therapy in RCC-FG2 cells. The max score was 16.41 .

FIG. 21 A is a chart showing dose dependent, normalized CTG signal levels in RCC-JF cells treated with varying concentrations of erastin and X1 . The data are normalized to DMSO. The X-axis shows X1 concentrations (pM).

FIG. 21 B is a chart showing Bliss synergy scores for X1 /erastin combination therapy in RCC-JF cells. The max score was 24.2.

FIG. 22A is a chart showing dose dependent, normalized CTG signal levels in U251 -MG cells treated with varying concentrations of erastin and P32. The data are normalized to DMSO.

FIG. 22B is a projection plot showing Bliss synergy scores for P32/erastin combination therapy in U251 -MG cells.

FIG. 22C is a chart showing Bliss synergy scores for X1 /erastin combination therapy in U251 -MG cells.

FIG. 23A is a chart showing dose dependent, normalized CTG signal levels in U251 -MG cells treated with varying concentrations of erastin and X1 . The data are normalized to DMSO.

FIG. 23B is a projection plot showing Bliss synergy scores for X1 /erastin combination therapy in U251 -MG cells.

FIG. 23C is a chart showing Bliss synergy scores for X1 /erastin combination therapy in U251 -MG cells. FIG. 24A is a chart showing Bliss synergy scores for P32/666-15 combination therapy in RCC-JF cells in FBS. The max score was 18.8.

FIG. 24B is a chart showing Bliss synergy scores for P32/666-15 combination therapy in RCC-JF cells in LDPS. The max score was 6.2.

FIG. 25A is a chart showing Bliss synergy scores for P32/fatostatin combination therapy in RCC- JF cells in FBS. The max score was 12.34.

FIG. 25B is a chart showing Bliss synergy scores for P32/fatostatin combination therapy in RCC- JF cells in LDPS. The max score was 5.88.

FIG. 26A is a chart showing Bliss synergy scores for P32/A-485 combination therapy in RCC-JF cells in FBS. The max score was 10.4.

FIG. 26B is a chart showing Bliss synergy scores for P32/ A-485 combination therapy in RCC-JF cells in LDPS. The max score was 8.52.

FIG. 27A is a chart showing Bliss synergy scores for P32/PF429242 combination therapy in RCC-JF cells in FBS. The max score was 2.66.

FIG. 27B is a chart showing Bliss synergy scores for P32/ PF429242 combination therapy in RCC-JF cells in LDPS. The max score was 3.04.

FIG. 28A is a chart showing Bliss synergy scores for X1/666-15 combination therapy in RCC-JF cells in FBS. The max score was 13.2.

FIG. 28B is a chart showing Bliss synergy scores for X1/666-15 combination therapy in RCC-JF cells in LDPS. The max score was 4.05.

FIG. 29A is a chart showing Bliss synergy scores for X1/fatostatin combination therapy in RCC- JF cells in FBS. The max score was 1 1 .83.

FIG. 29B is a chart showing Bliss synergy scores for X1/fatostatin combination therapy in RCC- JF cells in LDPS. The max score was 13.37.

FIG. 30A is a chart showing Bliss synergy scores for X1 /A-485 combination therapy in RCC-JF cells in FBS. The max score was 2.56.

FIG. 30B is a chart showing Bliss synergy scores for X1 / A-485 combination therapy in RCC-JF cells in LDPS. The max score was 0.98.

FIG. 31 A is a chart showing Bliss synergy scores for X1/PF429242 combination therapy in RCC- JF cells in FBS. The max score was 1 .067.

FIG. 31 B is a chart showing Bliss synergy scores for X1 / PF429242 combination therapy in RCC- JF cells in LDPS. The max score was 4.64.

FIG. 32A is a chart showing CTG signal levels for U251 -MG cells treated with P32 with or without a fatty acid (FA), SyntheChol (SC), or FA and SC supplement. The data are normalized to DMSO control.

FIG. 32B is a chart showing CTG signal levels for U251 -MG cells treated with X1 with or without a fatty acid (FA), SyntheChol (SC), or FA and SC supplement. The data are normalized to DMSO control.

FIG. 33 is a chart showing the results for the Chlp-qPCR assay examining the enrichment of MED1 on indicated gene loci. The enrichment of MED1 at promoter of typical SREBP-target genes ( FASN , SCD and HMGCR) induced by switching to 1 %LPDS medium was abolished after the treatment of P32 or X1 . The p-value was calculated by ANOVA followed by Dunnett's multiple comparisons test (1 %LPDS condition as the control) p < 0.0001 ^****, p<0.001 ^***, p<0.01 ^**, p<0.05 ^*, p>0.05 n.s.

FIG. 34 is a chart showing the results for the Chlp-qPCR assay examining the enrichment of Pol II on indicated gene loci. The enrichment of Pol II at promoter of typical SREBP-target genes ( FASN , SCD and HMGCR) induced by switching to 1 %LPDS medium was abolished after the treatment of C2 or C34. The p-value was calculated by ANOVA followed by Dunnett's multiple comparisons test (1 %LPDS condition as the control) p < 0.0001 ^****, p<0.001 ^***, p<0.01 ^**, p<0.05 ^*, p>0.05 n.s.

DETAILED DESCRIPTION

The invention provides compounds, pharmaceutical compositions containing them, and methods of their use in the treatment of diseases treatable through inhibition of an interaction between sterol regulatory element-binding protein 1 (SREBP1 ) and the KIX domain of mediator of RNA polymerase II transcription subunit 15 (MED15) or CREB-binding protein (CBP) (e.g., cancer or metabolic disorder). Without wishing to be bound by theory, compounds of the invention are believed to inhibit the interaction between SREBP1 and the KIX domain of CBP or MED15.

Compounds

The invention provides compounds that may be useful in the treatment of cancers or metabolic disorders. The compound may be an agent capable of inhibiting the binding of SREBP1 and the KIX domain of CBP or MED15 to inhibit the binding between SREBP1 and the KIX domain of MED15 or CBP. The agent may be a small molecule or an antibody capable of binding the KIX domain of CBP or MED15 to inhibit the binding between SREBP1 and the KIX domain of MED15 or CBP.

A small molecule of the invention may be a compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

R² is hydroxyl, optionally substituted C1 -6 alkoxy, or -N(R³)2, wherein each R³ is independently H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-10 cycloalkyl, optionally substituted Ce-io aryl C1-6 alkyl, or optionally substituted C1-9 heterocyclyl C1-6 alkyl, or both R³, together with the atom to which they are attached, combine to form an optionally substituted C1 -9 heterocyclyl.

In some embodiments, the compound of formula (I) is not a compound of any one of the following compounds:

and pharmaceutically acceptable salts thereof.

In certain embodiments, the compound of formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.

In particular embodiments, the compound of formula (I) is a compound of formula (IB):

or a pharmaceutically acceptable salt thereof.

A small molecule compound of the invention may be a compound of formula (II):

^<RV N

\^_Z'^R3

(ii)

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1 -6 alkyl; and

R^B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1 -9 heterocyclyl C1-6 alkyl; and R^c is H or optionally substituted C1-6 alkyl; or R^B and R^c combine to form an optionally substituted C1 -9 heterocyclyl. In some embodiments, the compound of formula (II) is not a compound of any one of the following compounds:

pharmaceutically acceptable salts thereof.

In certain embodiments, the compound of formula (II) is a compound of formula (II A) :

or a pharmaceutically acceptable salt thereof.

In further embodiments, a small molecule may be a compound selected from the group consisting of:

pharmaceutically acceptable salts thereof.

An agent of the invention may be an antibody or an antigen-binding fragment thereof. The making and use of therapeutic antibodies against a target antigen (e.g., KIX domain of CBP or MED15) is known in the art. See, e.g., Zhiqiang An (Editor), Therapeutic Monoclonal Antibodies: From Bench to Clinic. 1 st Edition. Wiley 2009, and also Greenfield (Ed.), Antibodies: A Laboratory Manual. (Second edition) Cold Spring Harbor Laboratory Press 2013, for methods of making recombinant antibodies, including antibody engineering, use of degenerate oligonucleotides, 5'-RACE, phage display, and mutagenesis; antibody testing and characterization; antibody pharmacokinetics and pharmacodynamics; antibody purification and storage; and screening and labeling techniques. Pharmaceutical Compositions

The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include a compound as described herein and a pharmaceutically acceptable excipient. In certain embodiments, the compound is a compound of formula (I) (e.g., a compound selected from the group consisting of compounds A1-A40, or a compound selected from the group consisting of compounds X1-X5). In some embodiments, the compound is a compound of formula (II) (e.g., a compound selected from the group consisting of compounds P1-P57).

The compounds described herein can also be used in the form of the free base, in the form of salts, zwitterions, solvates, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the invention. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof, may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds used in the methods described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

For human use, a compound of the invention can be administered alone or in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present invention thus can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of a compound of the invention into preparations which can be used pharmaceutically.

This invention also includes pharmaceutical compositions which can contain one or more pharmaceutically acceptable carriers. In making the pharmaceutical compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending upon the intended route of administration. The resulting compositions can include additional agents, e.g., preservatives.

The excipient or carrier is selected on the basis of the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21 ^st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents, e.g., talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents, e.g., methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6^th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

These pharmaceutical compositions can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy, 21 ^st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1 988-1999, Marcel Dekker, New York. Proper formulation is dependent upon the route of administration chosen. The formulation and preparation of such compositions is well-known to those skilled in the art of pharmaceutical formulation. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

Dosages

The dosage of the compound used in the methods described herein, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof, can vary depending on many factors, e.g., the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds used in the methods described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

A compound of the invention may be administered to the patient in a single dose or in multiple doses. When multiple doses are administered, the doses may be separated from one another by, for example, 1 -24 hours, 1 -7 days, 1 -4 weeks, or 1 -12 months. The compound may be administered according to a schedule or the compound may be administered without a predetermined schedule. An active compound may be administered, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 times per day, every 2^nd, 3^rd, 4^th, 5^th, or 6^th day, 1 , 2, 3, 4, 5, 6, or 7 times per week, 1 , 2, 3, 4, 5, or 6 times per month, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 times per year. It is to be understood that, for any particular subject, specific dosage regimes should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

While the attending physician ultimately will decide the appropriate amount and dosage regimen, an effective amount of a compound of the invention may be, for example, a total daily dosage of, e.g., between 0.05 mg and 3000 mg of any of the compounds described herein. Alternatively, the dosage amount can be calculated using the body weight of the patient. Such dose ranges may include, for example, between 10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

In the methods of the invention, the time period during which multiple doses of a compound of the invention are administered to a patient can vary. For example, in some embodiments doses of the compounds of the invention are administered to a patient over a time period that is 1 -7 days; 1 -12 weeks; or 1 -3 months. In other embodiments, the compounds are administered to the patient over a time period that is, for example, 4-1 1 months or 1 -30 years. In other embodiments, the compounds are administered to a patient at the onset of symptoms. In any of these embodiments, the amount of compound that is administered may vary during the time period of administration. When a compound is administered daily, administration may occur, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 times per day.

Formulations

A compound identified as capable of treating any of the conditions described herein, using any of the methods described herein, may be administered to patients or animals with a pharmaceutically- acceptable diluent, carrier, or excipient, in unit dosage form. The chemical compounds for use in such therapies may be produced and isolated by any standard technique known to those in the field of medicinal chemistry. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the identified compound to patients suffering from a bacterial infection. Administration may begin before the patient is symptomatic.

Exemplary routes of administration of the compounds (e.g., a compound of the invention), or pharmaceutical compositions thereof, used in the present invention include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. The compounds desirably are administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein formulated for treatment of the disorders described herein are also part of the present invention.

Formulations for Oral Administration

The pharmaceutical compositions contemplated by the invention include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate,

carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance. Any of a number of strategies can be pursued in order to obtain controlled release and the targeted plasma concentration versus time profile. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. In certain embodiments, compositions include biodegradable, pH, and/or temperature-sensitive polymer coatings.

Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl- polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.

The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Formulations for Buccal Administration

Dosages for buccal or sublingual administration typically are 0.1 to 500 mg per single dose as required. In practice, the physician determines the actual dosing regimen which is most suitable for an individual patient, and the dosage varies with the age, weight, and response of the particular patient. The above dosages are exemplary of the average case, but individual instances exist wherein higher or lower dosages are merited, and such are within the scope of this invention.

For buccal administration, the compositions may take the form of tablets, lozenges, etc.

formulated in a conventional manner. Liquid drug formulations suitable for use with nebulizers and liquid spray devices and electrohydrodynamic (EHD) aerosol devices will typically include a compound of the invention with a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is a liquid, e.g., alcohol, water, polyethylene glycol, or a perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of compounds of the invention. Desirably, this material is liquid, e.g., an alcohol, glycol, polyglycol, or a fatty acid. Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art (see, e.g., Biesalski, U.S. Pat. No. 5,1 12,598 and Biesalski, U.S. Pat. No. 5,556,61 1 , each of which is herein incorporated by reference).

Formulations for Nasal or Inhalation Administration

The compounds may also be formulated for nasal administration. Compositions for nasal administration also may conveniently be formulated as aerosols, drops, gels, and powders. The formulations may be provided in a single or multidose form. In the case of a dropper or pipette, dosing may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved, for example, by means of a metering atomizing spray pump.

The compounds may further be formulated for aerosol administration, particularly to the respiratory tract by inhalation and including intranasal administration. The compound will generally have a small particle size for example on the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant, e.g., a chlorofluorocarbon (CFC), for example,

dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant, e.g., lecithin. The dose of drug may be controlled by a metered valve. Alternatively, the active ingredients may be provided in a form of a dry powder, e.g., a powder mix of the compound in a suitable powder base, e.g., lactose, starch, and starch derivatives, e.g., hydroxypropylmethyl cellulose, and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.

Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, e.g., a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, e.g., compressed air or an organic propellant, e.g.,

fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.

Formulations for Parenteral Administration

The compounds described herein for use in the methods of the invention can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulation as described herein. The pharmaceutical formulation may also be administered parenterally (intravenous, intramuscular, subcutaneous or the like) in dosage forms or formulations containing conventional, non toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the invention may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1 ,3-butanediol, Ringer’s solution and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), herein incorporated by reference.

The parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration:

(1 ) “Drug Injection:” a liquid preparation that is a drug substance (e.g., a compound of the

invention), or a solution thereof;

(2) “Drug for Injection:” the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection;

(3) “Drug Injectable Emulsion:” a liquid preparation of the drug substance (e.g., a compound of the invention) that is dissolved or dispersed in a suitable emulsion medium;

(4) “Drug Injectable Suspension:” a liquid preparation of the drug substance (e.g., a compound of the invention) suspended in a suitable liquid medium; and

(5) “Drug for Injectable Suspension:” the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injectable suspension.

Exemplary formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21 ^st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31 ), published in 2013.

Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols, e.g., polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or

polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

The parenteral formulation can be formulated for prompt release or for sustained/extended release of the compound. Exemplary formulations for parenteral release of the compound include: aqueous solutions, powders for reconstitution, cosolvent solutions, oil/water emulsions, suspensions, oil- based solutions, liposomes, microspheres, and polymeric gels.

Methods of Use

The invention also provides methods of use of the agents of the invention and their

pharmaceutical compositions.

In some embodiments, a method of the invention is a method of treating cancer or a metabolic disorder in a subject in need thereof. Typically, the method includes the step of administering a therapeutically effective amount of an agent of the invention or a pharmaceutical composition of the invention. The cancer may be, e.g., melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer. The metabolic disorder may be, e.g., nonalcoholic steatohepatitis or a cardiovascular disease (e.g., hypercholesterolemia).

In certain embodiments, a method of the invention is a method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP in a subject in need thereof. Typically, the method includes the step of administering a therapeutically effective amount of an agent of the invention or a pharmaceutical composition of the invention.

In the methods described above, the compound or the pharmaceutical composition may be administered to the subject enterally (e.g., orally). Alternatively, the compound or the pharmaceutical composition may be administered to the subject parenterally (e.g., intramuscularly, intratumorally, intravenously, subcutaneously, buccally, sublingually, sublabially, by inhalation, intra-arterially, intraventricularly, intraspinally, intrathecally, intraorbitally, intracranially, or topically).

In further embodiments, a method of the invention is a method of killing a cancer cell. Typically, this method includes a step of contacting a cancer cell with the compound of the invention. The cancer cell may be in a subject (e.g., a human).

In certain embodiments, the compound is a compound of formula (I) (e.g., a compound selected from the group consisting of compounds A1-A40, or a compound selected from the group consisting of compounds X1-X5). In some embodiments, the compound is a compound of formula (II) (e.g., a compound selected from the group consisting of compounds P1-P57).

Advantageously, compounds disclosed herein may act synergistically with fatty acid/cholesterol homeostasis modulators or inducers of ferroprototic cell death in treating diseases, disorders, and conditions described herein or in killing cancer cells. Non-limiting examples of fatty acid/cholesterol homeostasis modulators include CREB/CBP-KIX inhibitors (e.g., 666-15), CBP/p300 HAT inhibitors (e.g., A-485), and SREBP1 site 1 protease inhibitors (e.g., PF429242). Methods disclosed herein may further include the use of CREB/CBP-KIX inhibitors (e.g., 666-15), CBP/p300 HAT inhibitors (e.g., A-485), fatostatin, and SREBP1 site 1 protease inhibitors (e.g., PF429242), and pharmaceutically acceptable salts thereof. Non-limiting examples of inducers of ferroptotic cell death include:

The compounds have the following structures:

666-1 5 fatostatin

erastin

Preparation of the Small Molecules

Small molecules of the invention may be prepared using reactions and techniques known in the

A non-limiting example of the preparation of a compound of formula (I) is as follows:

L = -CH=CH- or -CH₂CH₂

In the scheme above, R¹ and R² may be as described herein.

As shown above, compound A may be reacted with compound B (e.g., maleic anhydride, if L = -CH=CH-; or succinic anhydride, if L = -CH2CH2-) to Friedel-Crafts reaction conditions (e.g., in the presence of a Lewis acid (e.g., an oxophilic Lewis acid, such as AICI3)) to produce compound C.

Subsequent esterification (if R² in D is optionally substituted alkoxy) or amidation (if R² in D is -N(R³)2) of compound C may provide compound D. Amidation conditions are known in the art, for example, typical amidation conditions include the use of reagents, such as EDC/DMAP, EDC/HOBt, HATU/HOAt, or HBTU/HOAt. The esterification reaction conditions are known in the art. For example, esterification conditions may include Steglich esterification (e.g., EDC/DMAP) or treatment with /^'so-butyl chloroformate and /V-methylmorpholine to prepare an intermediate mixed anhydride, which is then reacted with a nucleophile. In the amidation and esterification reactions, EDC may be provided, for example, as EDC- HCI or as EDCI.

The following examples are meant to illustrate the invention. They are not meant to limit the invention in any way.

EXAMPLES

Example 1. Preparation of the Compounds

Small molecules of the invention may be prepared using reactions and techniques known in the art. Non-limiting examples of the preparation of the small molecules are provided below. Compounds X1-X5 and P1 -P57 are commercially available.

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance spectra were obtained on Bruker AVANCE spectrometer at 400 MHz for proton. Spectra are given in ppm (d) and coupling constants, J, are reported in Hertz. The solvent peak was used as the reference peak for proton spectra. LC-MS spectra were obtained on Agilent 1 100 HPLC LC-MS ion trap electrospray ionization (ESI) mass spectrometer.

A16

(E)-4-(4-cyclohexylphenyl)-4-oxobut-2-enoic acid (SB1-B-01-1)

The mixture of SM-1-1 (2.1 g, 13.1 mmol), SM-1-2 (1 .3 g, 13.3 mmol) and AlCh (2.6 g, 19.5 mmol) in dichloromethane (50 mL) was stirred at r.t overnight. The mixture was poured into ice (100 g), then extracted with ethyl acetate (150 mL c 3), the combined organic phase was washed with brine (80 mL x 3), dried with Na2SC>4, filtered and concentrated under vacuum, the residue was purified by prep- HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give X1 as light yellow solid (1 .4 g, yield 41 %). LCMS (m/z): 259 [M + H] ⁺.

(E)-methyl 4-(4-cyclohexylphenyl)-4-oxobut-2-enoate (A16)

The mixture of X1 (31 0 mg, 1 .20 mmol), EDC-HCI (346 mg, 1 .80 mmol), MeOH (5 mL) and dichloromethane (1 0 mL) was stirred at r.t overnight, after completion, the mixture was concentrated to remove the solvent, the residue was extracted with ethyl acetate (100 mL c 3), the combined organic phase was washed with brine (50 mL c 2), dried with Na2S04, filtered and concentrated under vacuum, the residue was purified by prep-HPLC (C1 8 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A16 as light yellow solid (120 mg, yield 37%). LCMS (m/z): 273 [M + H] ⁺; ¹ H NMR (CDCI3, 400 MHz): d 7.93 (m, 3 H), 7.35 (d, J = 8.4 Hz, 2 H), 6.89 (d, J = 15.6 Hz, 1 H), 3.85 (s, 3 H), 2.59m (m, 1 H), 1 .72-1 .96 (m, 5 H), 1 .20-1 .51 (m, 5 H).

A17

(E)-4-(4-cyclohexylphenyl)-N-methyl-4-oxobut-2-enamide (A17)

The mixture of X1 (330 mg, 1 .28 mmol), HOBt (210 mg, 1 .55 mmol), dichloromethane (10 ml_), THF (15 ml_) was stirred at r.t for 10 min, then EDC-HCI (368 mg, 1 .92 mmol) was added, further stirred for 1 h, then MeNH2-HCI (180 mg, 2.67 mmol) and triethylamine (2 ml_) was added, stirred at r.t for 3 h, after completion, extracted with ethyl acetate (150 ml_ 2), the organic phase was washed with 2 M HCI (50 ml_ 2), brine (50 ml_ 2), dried with Na2S04, filtered, removed the solvent, the residue was purified by prep-HPLC (C1 8 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A17 (off-white solid, 65 mg, yield 19 %). LCMS (m/z): 272 [M + H] ⁺; ¹ H NMR (DMSO-afe, 400 MHz) : d 8.54 (d, J = 3.6 Hz, 1 H), 7.95 (dd, J1 = 8.0 Hz, J₂ = 1 .2 Hz, 2 H), 7.74 (dd, J1 = 15.2 Hz, J₂ = 1 .6 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 6.95 (d, J = 15.2 Hz, 1 H), 2.73 (d, 3 H), 2.61 (t, J = 10.0 Hz, 1 H), 1 .67-1 .86 (m, 5 H), 1 .18-1 .51 (m, 5 H).

A18

(prop-2-ynyloxy)benzene (SB1 -B-03-1 )

The mixture of SM-03-1 (1 .03 g, 10.9 mmol), SM-3-2 (2.0 g, 16.8 mmol), K2CO3 (2.2 g, 15.9 mmol) and acetone (50 ml_) was stirred at 55°C for 18 h, after completion, concentrated to remove the solvent, extracted with ethyl acetate (1 00 ml_ 3), the organic phase was washed with brine (50 ml_ 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to obtain A18-1 (light yellow oil, 1 .10 g, yield 76%). LCMS (m/z): 133 [M + H] ⁺.

(E)-4-oxo-4-(4-(prop-2-ynyloxy)phenyl)but-2-enoic acid (A18)

To a solution of A18-1 (412 mg, 3.12 mmol), SM-3-3 (310 mg, 3.16 mmol) in dichloromethane (10 mL) was added AICI3 (630 mg, 4.72 mmol) under 0°C, and the mixture was stirred at 0°C -r.t overnight, then added H2O (50 mL), extracted with ethyl acetate (100 mL c 3), the organic phase was washed with brine (50 mL 3), dried with Na2SC>4, purified by prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A18 (light yellow solid, 180 mg, yield 25%). LCMS (m/z): 231 [M + H] ⁺; ¹ H NMR (DMSO-cfe, 500 MHz): d 13.14 (s, 1 H), 8.06 (d, J = 9.0 Hz, 2 H), 7.90 (d, J = 15.5 Hz, 1 H), 7.15 (d, J = 9.0 Hz, 2 H), 6.67 (d, J = 15.5 Hz, 2 H), 4.95 (d, J = 2.5 Hz, 2 H), 3.66 (t, J = 2.5 Hz, 2H). A19

4-oxo-4-(4-(prop-2-ynyloxy)phenyl)butanoic acid (A19)

To a solution of A18-1 (410 mg, 3.10 mmol), SM-4-1 (330 mg, 3.30 mmol) in dichloromethane (15 mL) was added AlC (650 mg, 4.87 mmol), then the mixture was stirred at r.t overnight, after completion, added H2O (50 mL) to quench the reaction, extracted with ethyl acetate (100 mL x 3), the organic phase was washed with brine (50 mL x 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to obtain A19 (white solid, 370 mg, yield 51 %). LCMS (m/z): 233 [M + H] ⁺; ¹ H NMR (DMSO-cfe, 400 MHz): d 12.13 (s, 1 H), 7.98 (d, J = 8.0 Hz, 2 H), 7.1 0 (d, J = 8.0 Hz, 2 H), 4.92 (s, 2 H), 3.64 (s, 1 H), 3.20 (t, J = 6.0 Hz, 2 H), 2.56 (t, J = 6.0 Hz, 2 H).

A20

1 -(4-(piperidin-1 -yl)phenyl)ethanone (A20-1 )

The mixture of SM-5-2 (2.1 g, 10.6 mmol), SM-5-1 (3.0 g, 35.2 mmol), Pd2(dba)3 (970 mg, 1 .06 mmol), BINAP (1 .4 g, 2.25 mmol), CS2CO3 (7.5 g, 23.0 mmol) and 1 ,2-dimethoxyethane (50 mL) was stirred at 90°C overnight, after completion, concentrated to remove the solvent, extracted with ethyl acetate (100 mL x 3), the organic phase was washed with brine (80 mL x 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified with silica gel (PE/ ethyl acetate = 8/1 ) to give A20-1 (light yellow solid, 1 .10 g, yield 51 %). LCMS (m/z): 204 [M + H] ⁺.

(E)-4-oxo-4-(4-(piperidin-1 -yl)phenyl)but-2-enoic acid (A20)

The mixture of SB1-B-05-1 (360 mg, 1 .77 mmol), SM-5-3 (265 mg, 3.58 mmol) and AcOH (6 mL) was stirred at 105 °C overnight, after completion, concentrated to remove the solvent, the residue was purified by C18 column (CH3CN/H2O, containing 0.05% trifluoroacetic acid) to obtain A20 (orange solid, 40 mg, yield 9%). LCMS (m/z): 260 [M + H] ⁺; ¹ H NMR (DMSO-afe, 400 MHz): d 7.84-7.93 (m, 3 H), 6.99 (d, J = 9.2 Hz, 2 H), 6.62 (d, J = 15.6 Hz, 1 H), 3.45 (m, 4 H), 1 .59 (m, 6 H).

1 -(3-cyclohexenylphenyl)ethanone ( A21 -1 )

The mixture of SM-6-2 (1 .70 g, 6.91 mmol), SM-6-1 (8 ml_), Pd(PP i3)4 (840 mg, 0.727 mmol), K2CO3 (2.0 g, 14.5 mmol), THF (15 ml_) and H2O (5 ml_) was stirred at 70°C overnight, after completion, extracted with ethyl acetate (100 ml_ 3), the organic phase was washed with brine (50 ml_ 2), dired with Na2SC>4, diltered, removed the solvent, the residue was purified by prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A21-1 (light brown oil, 500 mg, yield 27%). LCMS (m/z): 201 [M + H] ⁺.

1 -(3-cyclohexylphenyl)et hanone ( A21 -2)

The mixture of A21-1 (500 mg, 2.50 mmol), THF (10 mL), MeOH (1 0 mL) and Pd/C (105 mg) was stirred at r.t overnight under H2 (1 atm), after completion, filtered, concentrated to remove the solvent to give SB1-B-06-2 (light brown oil, 480 mg, yield 95%). LCMS (m/z): 203 [M + H] ⁺.

(E)-4-(3-cyclohexylphenyl)-4-oxobut-2-enoic acid (A21)

The mixture of A21-2 (450 mg, 2.22 mmol), SM-6-3 (330 mg, 4.46 mmol) and AcOH (8 mL) was stirred at 105°C overnight, after completion, concentrated to remove the solvent, the residue was purified by C18 column (CH3CN/H2O, containing 0.05% trifluoroacetic acid) to obtain A21 (off-white solid, 80 mg, yield 14%). LCMS (m/z): 259 [M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 13.20 (bs, 1 H), 7.90 (d, J = 15.2 Hz, 1 H), 7.85 (d+d, 2 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 1 H), 6.68 (d, J = 15.6 Hz, 1 H), 2.63 (t, J = 1 1 .2 Hz, 1 H), 1 .66-1 .89 (m, 5 H), 1 .19-1 .54 (m, 5 H).

A22

1 -(4-morpholinophenyl)ethanone (A22-1 )

The mixture of SM-5-2 (2.1 g, 10.6 mmol), SM-5-1 (3.0 g, 34.4 mmol), Pd2(dba)3 (966 mg, 1 .05 mmol), BINAP (1 .32 g, 2.12 mmol), CS2CO3 (7.6 g, 23.3 mmol) and DME (50 ml_) was stirred at 90°C overnight, after completion, concentrated to remove the solvent, extracted with ethyl acetate (1 00 ml_ 3), the organic phase was washed with brine (80 ml_ 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified with silica gel (PE/ ethyl acetate = 6/1 ) to give A22-1 (yellow solid, 1 .05 g, yield 48%). LCMS (m/z): 206 [M + H] ⁺. (E)-4-(4-morpholinophenyl)-4-oxobut-2-enoic acid (A22)

The mixture of SB1-B-07-1 (350 mg, 1 .71 mmol), SM-7-3 (253 mg, 3.42 mmol) and AcOH (8 mL) was stirred at 105°C overnight, after completion, concentrated to remove the solvent, the residue was purified by (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to obtain A22 (orange solid, 70 mg, yield 16%). LCMS (m/z): 262 [M + H] ⁺; ¹ H NMR (DMSO-afe, 500 MHz): d 13.08 (bs, 1 H), 7.94 (d, J = 9.0 Hz, 2 H), 7.89 (d, J = 15.5 Hz, 1 H), 7.03 (d, J = 9.5 Hz, 2 H), 6.63 (d, J = 15.5 Hz, 1 H), 3.73 (t, J = 5.0 Hz, 4 h), 3.36 (t, J = 5.0 Hz, 4 H).

(E)-4-oxo-4-(4-phenoxyphenyl)but-2-enoic acid (A23)

To a solution of SM-8-1 (505 mg, 2.97 mmol), SM-8-2 (300 mg, 3.06 mmol) in dichloromethane (20 mL) was added AICI3 (600 mg, 4.50 mmol), the mixture was stirred at r.t overnight , after completion, added H2O (50 mL) to quench the reaction, extracted with ethyl acetate (100 mL c 3), the organic phase was washed with brine (50 mL), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-HPLC (C1 8 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A23 (white solid, 80 mg, yield 10%). LCMS (m/z): 269 [M + H] ⁺; ¹ H NMR (DMSO-afe, 400 MHz): d 13.20 (bs, 1 H), 8.08 (d, J = 8.8 Hz, 2 H), 7.87 (d, J = 15.6 Hz, 1 H), 7.49 (t, J = 8.0 Hz, 2 H), 7.28 (t, J = 7.2 Hz, 1 H), 7.1 7 (d, J = 7.6 Hz, 2 H), 7.08 (d, J = 8.4 Hz, 2 H), 6.68 (d, J = 15.2 Hz, 1 H).

A24

(E)-N-benzyl-4-(4-cyclohexylphenyl)-4-oxobut-2-enamide (A24)

The mixture of 1 (300 mg, 1 .16 mmol), HOBt (200 mg, 1 .48 mmol), dichloromethane (6 ml_), THF (6 ml_) was stirred at r.t for 10 min, then EDC-HCI (400 mg, 2.09 mmol) was added, further stirred for 0.5 h, then benzylamine (1 50 mg, 1 .40 mmol) was added, stirred at r.t for 3 h, after completion, extracted with ethyl acetate (80 ml_ 3), the organic phase was washed with brine (50 ml_ 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-HPLC (C1 8 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A24 (off-white solid, 31 mg, yield 7.7 %). LCMS (m/z): 348 [M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 9.09 (t, J = 2.0 Hz, 1 H), 7.95 n(d, J = 8.0 Hz, 2 H), 7.80 (d, J = 1 1 .4 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.27-7.37 (m, 5 H), 7.32 (d, J = 15.6 Hz, 1 H), 4.42 (d, J = 6.0 Hz, 2 H), 2.61 (m, 1 H), 1 .69-1 .81 (m, 5 H), 1 .26-1 .45 (m, 5 H).

(E)-4-(4-cyclohexylphenyl)-N-cyclopropyl-4-oxobut-2-enamide (A25)

The mixture of 1 (310 mg, 1 .20 mmol), HOBt (205 mg, 1 .52 mmol), dichloromethane (6 ml_), THF (6 ml_) was stirred at r.t for 20 min, then EDC-HCI (400 mg, 2.09 mmol) was added, further stirred for 1 h, then cyclopropanamine (1 00 mg, 1 .75 mmol) was added, stirred at r.t for 3 h, after completion, extracted with ethyl acetate (80 ml_ 3), the organic phase was washed with brine (50 ml_ 2), dried with Na2S04, filtered, removed the solvent, the residue was purified by prep-HPLC (C1 8 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A25 (off-white solid, 48 mg, yield 13 %). LCMS (m/z): 298 [M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 8.64 (d, J = 4.4 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 2 H), 7.73 (d, J =

15.6 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 2 H), 6.88 (d, J =15.6 Hz, 1 H), 2.78-2.82 (m, 1 H), 2.61 (m, 1 H), 1 .69- 1 .81 (m, 5 H), 1 .26-1 .45 (m, 5 H), 0.70-0.74(m, 2 H), 0.46-0.51 (m, 2 H).

A26

(E)-4-(4-cyclohexylphenyl)-N-((1-methylpiperidin-4-yl)methyl)-4-oxobut-2-enamide (A26)

The mixture of 1 (300 mg, 1 .16 mmol), HOBt (220 mg, 1 .63 mmol), dichloromethane (6 ml_), THF (6 ml_) was stirred at r.t for 10 min, then EDC-HCI (400 mg, 2.09 mmol) was added, further stirred for 0.5 h, then (1 -methylpiperidin-4-yl)methanamine (1 60 mg, 1 .25 mmol) was added, stirred at r.t for 3 h, after completion, extracted with ethyl acetate (100 ml_ 3), the organic phase was washed with brine (50 ml_ 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-TLC

(dichloromethane/MeOH = 8/1 ) and prep-HPLC (C18 column, CH3CN/H2O, containing 0.05%

trifluoroacetic acid) to give A26 (off-white solid, 27 mg, yield 6.3 %). LCMS (m/z): 369 [M + H] ⁺; ¹ H NMR (DMSO-cfe, 400 MHz): d 7.86 (d, J = 8.4 Hz, 2 H), 7.79 (d, J = 15.6 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 2 H),

6.91 (d, J =15.6 Hz, 1 H), 3.42-3.45 (m, 2 h), 3.1 7-3.21 n (m, 2 H), 2.84-2.92 (m, 2 H), 2.76 (s, 3 H), 2.53 (m, 1 H), 1 .20-1 .94 (m, 15 H).

A27

(E)-4-(4-cyclohexylphenyl)-N-isobutyl-4-oxobut-2-enamide (A27)

The mixture of 1 (300 mg, 1 .16 mmol), HOBt (200 mg, 1 .48 mmol), dichloromethane (6 mL), THF (6 mL) was stirred at r.t for 10 min, then EDC-HCI (380 mg, 1 .98 mmol) was added, further stirred for 0.5 h, then 2-methylpropan-1 -amine (100 mg, 1 .37 mmol) was added, stirred at r.t overnight, after completion, extracted with ethyl acetate (80 mL x 3), the organic phase was washed with brine (50 mL c 2), dried with Na2S04, filtered, removed the solvent, the residue was purified by prep-TLC (petroleum ether/ethyl acetate = 8/1 ) and prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A27 (off-white solid, 52 mg, yield 14 %). LCMS (m/z): 314 [M + H] ⁺; ¹ H NMR (DMSO-cfe, 400 MHz): d 8.56 (t, J = 2.0 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 2 H), 7.73 (d, J = 15.6 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.02 (d, J =1 5.6 Hz, 1 H), 3.03 (t, J = 6.0 Hz, 2 H), 2.61 (m, 1 H), 1 .69-1 .81 (m, 5 H), 1 .23-1 .45 (m, 5 H), 0.89 (s, 3 H), 0.87 (s, 3 H).

A28

(E)-tert-butyl 4-((4-(4-cyclohexylphenyl)-4-oxobut-2-enamido)methyl)piperidine-1- carboxylate (3)

The mixture of 1 (300 mg, 1 .16 mmol), HOBt (200 mg, 1 .48 mmol), dichloromethane (6 ml_), THF (6 ml_) was stirred at r.t for 20 min, then EDC-HCI (400 mg, 2.09 mmol) was added, further stirred for 1 h, then 2 (295 mg, 1 .38 mmol) was added, stirred at r.t o/n, after completion, extracted with ethyl acetate (100 mL x 3), the organic phase was washed with brine (50 ml_ c 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give 3 (light brown solid, 45 mg, yield 8.6 %). LCMS (m/z): 477 [M + Na] ⁺.

(E)-4-(4-cyclohexylphenyl)-4-oxo-N-(piperidin-4-ylmethyl)but-2-enamide (A28)

The mixture of 1 (32 mg, 0.0704 mmol), trifluoroacetic acid (1 mL) and dichloromethane (5 mL) was stirred at r.t for 2 h, concentrated to remove the solvent, the residue was purified by prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A28 (off-white solid, 15 mg, yield 60%). LCMS (m/z): 355 [M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 7.87 (d, J = 8.0 Hz, 2 H), 7.80 (d, J = 15.2 Hz, 1 H), 7.31 (d, J = 8.04 Hz, 2 H), 6.91 (d, J =1 5.2 Hz, 1 H), 3.31 (d, J = 12.8 Hz, 2 H), 3.18-3.21 (m, 1 H), 2.84-2.92 (m, 2 H), 2.53 (m, 1 H), 1 .66-1 .90 (m, 9 H), 1 .20-1 .41 (m, 8 H).

A29

(E)-4-(4-cyclohexylphenyl)-N,N-dimethyl-4-oxobut-2-enamide (A29)

The mixture of 1 (254 mg, 0.983 mmol), HOBt (150 mg, 1 .1 1 mmol), dichloromethane (5 ml_),

THF (5 ml_) was stirred at r.t for 10 min, then EDC-HCI (400 mg, 2.09 mmol) was added, further stirred for 10 min, then dimethylamine hydrochloride (80 mg, 0.981 mmol) was added, stirred at r.t overnight, after completion, extracted with ethyl acetate (50 ml_ 2), the organic phase was washed with brine (30 ml_ 3), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-HPLC (C1 8 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A29 (off-white solid, 1 12 mg, yield 40 %).

LCMS (m/z): 286[M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 7.96 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 15.2 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.40 (d, J =1 5.2 Hz, 1 H), 3.1 1 (s, 3 H), 2.95 (s, 3 H), 2.61 (t, J = 10.4 Hz, 1 H), 1 .69-1 .81 (m, 5 H), 1 .23-1 .45 (m, 5 H). 3.31 (d, J = 12.8 Hz, 2 H), 3.18-3.21 (m, 1 H), 2.84-2.92 (m, 2 H), 2.53 (m, 1 H), 1 .66-1 .90 (m, 9 H), 1 .20-1 .41 (m, 8 H).

A10

(E)-tert-butyl 4-(4-(4-cyclohexylphenyl)-4-oxobut-2-enoyl)piperazine-1 -carboxylate (3)

The mixture of 1 (300 mg, 1 .16 mmol), HOBt (200 mg, 1 .48 mmol), dichloromethane (6 ml_), THF (6 ml_) was stirred at r.t for 20 min, then EDC-HCI (400 mg, 2.09 mmol) was added, further stirred for 0.5 h, then 2 (250 mg, 1 .34 mmol) was added, stirred at r.t o/n, after completion, extracted with ethyl acetate (80 ml_ 3), the organic phase was washed with brine (50 ml_ 2), dried with Na2S04, filtered, removed the solvent, the residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1 /1 ) and prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give 3 (light brown solid, 50 mg, yield 10 %). LCMS (m/z): 449 [M + Na] ⁺.

(E)-1 -(4-cyclohexylphenyl)-4-(piperazin-1 -yl)but-2-ene-1 ,4-dione (A10)

The mixture of 1 (38 mg, 0.0891 mmol), trifluoroacetic acid (1 mL) and dichloromethane (4 mL) was stirred at r.t for 3 h, concentrated to remove the solvent, the residue was purified by prep-HPLC(C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A10 (off-white solid, 16 mg, yield 55%). LCMS (m/z): 327 [M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz) : d 7.88 (d, J = 8.4 Hz, 2 H), 7.82 (d, J =

15.2 Hz, 1 H), 7.41 (d, J = 15.2 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 3.85 (t, J = 4.8 Hz, 4 H), 3.21 (t, J = 1 .6 Hz, 4 H), 2.52 (m, 1 H), 1 .66-1 .78 (m, 5 H), 1 .23-1 .41 (m, 5 H).

(E)-tert-butyl 4-((4-(4-cyclohexylphenyl)-4-oxobut-2-enamido)methyl)piperidine-1- carboxylate (SM-3)

The mixture of (E)-4-(4-cyclohexylphenyl)-4-oxobut-2-enoic acid (1 g, 3.87 mmol), tert-butyl 4- (aminomethyl)piperidine-l -carboxylate (829 mg, 3.87 mmol), EDCI (1 .2 g, 7.74 mmol) and HOBt (1 .05 g, 7.74 mmol) in dichloromethane/THF (30 ml_/30 ml_) was stirred at rt for 2h. The solvent was removed under reduced pressure and the product was purified by flash column chromatography (ethyl acetate/PE = 20%~40%) to give (E)-tert-butyl 4-((4-(4-cyclohexylphenyl)-4-oxobut-2-enamido)methyl)piperidine-1 - carboxylate (1 .6 g, yield: 90 %) as a yellow solid. ESI-LCMS (m/z): 355.2 [M-100+H]⁺.

(E)-4-(4-cyclohexylphenyl)-4-oxo-W-(piperidin-4-ylmethyl)but-2-enamide (SM-4)

To a solution of (E)-tert-butyl 4-((4-(4-cyclohexylphenyl)-4-oxobut-2-enamido)methyl)piperidine-1 - carboxylate (1 .6 g, 3.52 mmol) in dichloromethane (1 0 ml_) was added trifluoroacetic acid (2 ml_). The mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure to give (E)-4-(4- cyclohexylphenyl)-4-oxo-A/-(piperidin-4-ylmethyl)but-2-enamide (crude 2.8 g) as a dark green oil. ESI- LCMS (m/z): 355.2 [M+H]⁺.

(E)-/V-((1-acetylpiperidin-4-yl)methyl)-4-(4-cyclohexylphenyl)-4-oxobut-2-enamide (A30)

The mixture of (E)-4-(4-cyclohexylphenyl)-4-oxo-A/-(piperidin-4-ylmethyl)but-2-enamide (200 mg, 0.56 mmol), acetyl chloride (66 mg, 0.84 mmol) and A/,A/-diisopropylethylamine (145 mg, 1 .12 mmol) in dichloromethane/THF (10 mL/10 mL) was stirred at rt overnight. The product was purified by Prep-HPLC to give (E)-A/-((1 -acetylpiperidin-4-yl)methyl)-4-(4-cyclohexylphenyl)-4-oxobut-2-enamide (60 mg, yield: 26 %) as a white solid. ESI-LCMS (m/z): 397.2 [M+H]⁺. ¹ H NMR (400 MHz, DMSO-cfe) d 8.64 (t, J = 5.5 Hz,

1 H), 7.95 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 15.3 Hz, 1 H), 7.42 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 15.3 Hz, 1 H), 4.35 (t, J = 14.0 Hz, 1 H), 3.80 (d, J = 13.3 Hz, 1 H), 3.12 (t, J = 5.8 Hz, 2H), 2.98 (t, J = 12.3 Hz, 1 H), 2.59 (s, 1 H), 1 .96 (s, 3H), 1 .89 - 1 .56 (m, 8H), 1 .51 - 0.90 (m, 8H) ppm. (E)-/V-((1-benzylpiperidin-4-yl)methyl)-4-(4-cyclohexylphenyl)-4-oxobut-2-enamide (A32)

The mixture of (E)-4-(4-cyclohexylphenyl)-4-oxo-A/-(piperidin-4-ylmethyl)but-2-enamide (200 mg, 0.56 mmol), (bromomethyl)benzene (144 mg, 0.84 mmol) and A/,A/-diisopropylethylamine (145 mg, 1 .12 mmol) in dichloromethane/THF (10 ml_/1 O mL) was stirred at rt overnight. The product was purified by Prep-HPLC to give (E)-A/-((1 -benzylpiperidin-4-yl)methyl)-4-(4-cyclohexylphenyl)-4-oxobut-2-enamide (15 mg, yield: 6 %) as a white solid. ESI-LCMS (m/z): 445.2 [M+H]⁺. ¹ H NMR (400 MHz, DMSO-cfe, HCOOH salt) d 8.58 (t, J = 5.7 Hz, 1 H), 8.19 (s, 1 H), 7.94 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 15.3 Hz, 1 H), 7.42 (d, J = 8.2 Hz, 2H), 7.34 - 7.23 (m, 5H), 7.00 (d, J = 15.3 Hz, 1 H), 3.45 (s, 2H), 3.10 (t, J = 6.2 Hz, 2H), 2.80 (d, J = 1 1 .1 Hz, 2H), 2.62 (d, J = 9.0 Hz, 1 H), 1 .93 - 1 .61 (m, 9H), 1 .48 - 1 .17 (m, 8H) ppm.

(E)-4-(4-cyclohexylphenyl)-4-oxo-W-((1-(prop-2-ynyl)piperidin-4-yl)methyl)but-2-enamide

(A33)

The mixture of (E)-4-(4-cyclohexylphenyl)-4-oxo-A/-(piperidin-4-ylmethyl)but-2-enamide (200 mg, 0.56 mmol), (3-bromoprop-1 -yne (100 mg, 0.84 mmol) and A/,A/-diisopropylethylamine (145 mg, 1 .12 mmol) in dichloromethane/THF (10 ml_/10 ml_) was stirred at rt overnight. The product was purified by Prep-HPLC to give (E)-4-(4-cyclohexylphenyl)-4-oxo-A/-((1 -(prop-2-ynyl)piperidin-4-yl)methyl)but-2- enamide (15 mg, yield: 6 %) as a light yellow solid. ESI-LCMS (m/z): 393.3 [M+H]⁺. ¹ H NMR (400 MHz, DMSO-cfe) d 8.61 (d, J = 5.0 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 2H), 1.1 A (d, J = 15.3 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 15.3 Hz, 1 H), 3.1 9 - 3.05 (m, 3H), 2.78 (d, J = 1 1 .0 Hz, 2H), 2.61 (t, J = 10.1 Hz,

1 H), 2.07 (t, J = 1 1 .0 Hz, 2H), 1 .96 - 0.80 (m, 17H) ppm.

A31 , A34, A35, A36

(E)-4-(4-cyclohexylphenyl)-4-oxo-W-((tetrahydro-2H-pyran-4-yl)methyl)but-2-enamide (A31)

The mixture of (E)-4-(4-cyclohexylphenyl)-4-oxobut-2-enoic acid (200 mg, 0.77 mmol),

(tetrahydro-2H-pyran-4-yl)methanamine (88 mg, 0.77 mmol), EDCI (239 mg, 1 .54 mmol) and HOBt (208 mg, 1 .54 mmol) in dichloromethane/THF (10 ml_/10 ml_) was stirred at rt for 2h. The product was purified by Prep-HPLC to give (E)-4-(4-cyclohexylphenyl)-4-oxo-A/-((tetrahydro-2H-pyran-4-yl)methyl)but-2- enamide (30 mg, yield: 1 1 %) as a white solid. ESI-LCMS (m/z): 356.2 [M+H]⁺. ¹ H NMR (400 MHz, DMSO-cfe) d 8.61 (d, J = 5.4 Hz, 1 H), 7.95 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 15.3 Hz, 1 H), 7.43 (d, J = 8.2

Hz, 2H), 7.01 (d, J = 15.3 Hz, 1 H), 3.84 (d, J = 1 1 .2 Hz, 2H), 3.26 (t, J = 12.3 Hz, 2H), 3.10 (t, J = 6.2 Hz, 2H), 2.61 (t, J = 10.1 Hz, 1 H), 1 .80 - 1 .10 (m, 15H) ppm.

(E)-4-(4-cyclohexylphenyl)-/V-((1-methylpiperidin-3-yl)methyl)-4-oxobut-2-enamide (A34)

The mixture of (E)-4-(4-cyclohexylphenyl)-4-oxobut-2-enoic acid (200 mg, 0.77 mmol), (1 - methylpiperidin-3-yl)methanamine (99 mg, 0.77 mmol), EDCI (239 mg, 1 .54 mmol) and HOBt (208 mg,

1 .54 mmol) in dichloromethane/THF (10 ml_/10 ml_) was stirred at rt for 2h. The product was purified by Prep-HPLC to give (E)-4-(4-cyclohexylphenyl)-/V-((1 -methylpiperidin-3-yl)methyl)-4-oxobut-2-enamide (70 mg, yield : 24 %) as a white solid. ESI-LCMS (m/z): 369.2 [M+H]⁺. ¹ H NMR (400 MHz, DMSO-cfe, HCOOH salt) d 8.64 (s, 1 H), 8.26 (s, 1 H), 7.94 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 15.3 Hz, 1 H), 7.42 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 1 5.3 Hz, 1 H), 3.18 - 3.02 (m, 2H), 2.85 - 2.77 (m, 2H), 2.60 (t, J = 1 0.2 Hz, 1 H), 2.27 (s, 3H), 2.08 (t, J = 10.7 Hz, 1 H), 1 .93 - 0.86 (m, 16H) ppm. (E)-1-(4-cyclohexylphenyl)-4-(4-phenylpiperazin-1-yl)but-2-ene-1 ,4-dione (A36)

To a solution of (E)-4-(4-cyclohexylphenyl)-4-oxobut-2-enoic acid (200 mg, 0.77 mmol), 1 - phenylpiperazine (124 mg, 0.77 mmol), EDCI (239 mg, 1 .54 mmol) and HOBt (208 mg, 1 .54 mmol) in dichloromethane/THF (10 ml_/10 ml_) was stirred at rt for 2h. The product was purified by Prep-HPLC to give (E)-1 -(4-cyclohexylphenyl)-4-(4-phenylpiperazin-1 -yl)but-2-ene-1 ,4-dione (100 mg, yield: 32 %) as a yellow solid. ESI-LCMS (m/z) : 403.2 [M+H]⁺. ¹ H NMR (400 MHz, DMSO-de) d 7.98 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 15.2 Hz, 1 H), 7.51 - 7.42 (m, 3H), 7.24 (t, J = 7.8 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 6.82 (t, J = 7.2 Hz, 1 H), 3.74 (d, J = 4.2 Hz, 4H), 3.18 (d, J = 4.4 Hz, 4H), 2.61 (t, J = 10.7 Hz, 1 H), 1 .81 - 1 .70 (m, 5H), 1 .49 - 1 .23 (m, 5H) ppm.

(E)-tert-butyl 3-((4-(4-cyclohexylphenyl)-4-oxobut-2-enamido)methyl)piperidine-1- carboxylate (A35-1)

The mixture of (E)-4-(4-cyclohexylphenyl)-4-oxobut-2-enoic acid (200 mg, 0.77 mmol), tert-butyl 3-(aminomethyl)piperidine-1 -carboxylate (239 mg, 0.77 mmol), EDCI (239 mg, 1 .54 mmol) and HOBt (208 mg, 1 .54 mmol) in dichloromethane/THF (10 ml_/10 ml_) was stirred at rt for 2h. The product was purified by Prep-HPLC to give (E)-tert-butyl 3-((4-(4-cyclohexylphenyl)-4-oxobut-2- enamido)methyl)piperidine-1 -carboxylate (170 mg, yield: 48 %) as a yellow oil. ESI-LCMS (m/z): 355.2 [M-100+H]⁺.

(E)-4-(4-cyclohexylphenyl)-4-oxo-W-(piperidin-3-ylmethyl)but-2-enamide (A35)

To a solution of (E)-tert-butyl 3-((4-(4-cyclohexylphenyl)-4-oxobut-2-enamido)methyl)piperidine-1 - carboxylate (1 70 mg, 0.37 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at rt for 2h. The solvent was removed under reduced pressure and the product was purified by Prep-HPLC to give (E)-4-(4-cyclohexylphenyl)-4-oxo-A/-(piperidin-3-ylmethyl)but-2-enamide (80 mg, yield: 60 %) as a white solid. ESI-LCMS (m/z): 355.3 [M+H]⁺. ¹ H NMR (400 MHz, DMSO-cfe) d 8.73 (s, 1 H), 7.95 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 15.2 Hz, 1 H), 7.43 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 15.4 Hz, 1 H), 3.27 - 3.06 (m, 5H), 2.76 (t, J = 1 1 .8 Hz, 1 H), 2.60 (t, J = 1 1 .8 Hz, 2H), 1 .92 - 1 .68 (m, 7H), 1 .64 - 1 .12 (m, 8H) ppm.

A37

4-carbamoyl-1-(2,4-dinitrophenyl)pyridinium (3)

The mixture of 1 (2.0 g, 16.4 mmol), 2 (4.2 g, 20.7 mmol) was stirred at 100°C for 5 h, the result solid was suspended in MeOH and stirred at r.t for 2 h, then filtered, washed with MeOH to get 3 (light yellow solid, 2.5 g, yield 47%). 2199 [M - Cl] ⁺.

4-carbamoyl-1-phenylpyridinium (4)

The mixture of 3 (1 .8 g, 5.54 mmol), aniline (1 .4 g, 15.0 mmol) in MeOH (40 ml_) was stirred at 50°C o/n, then concentrated to remove the solvent, the residue was suspended in acetone (50 ml_), filtered, the solid was washed with acetone to obtain 4 (yellow solid, 1 .2 g, yield 92%). LCMS (m/z): 199 [M - Cl] ⁺.

1-phenylpiperidine-4-carboxamide (5)

The mixture of 4 (1 .5 g, 6.39 mmol), Pd/C (300 mg) in MeOH (50 ml_) was stirred at r.t under H2 (1 atm) for 16 h, then filtered, concentrated to remove the solvent, the residue was purified by flash column (dichloromethane/MeOH = 15/1 ) to give 6 (light brown solid, 400 mg, yield 31 %). LCMS (m/z): 205 [M + H] ⁺.

(1-phenylpiperidin-4-yl)methanamine (6)

To the mixture of 5 (104 mg, 0.509 mmol) in THF (10 mL) was added AIUH4 (1 M, 4 mL, 4.0 mmol) dropwise, then stirred at 50°C overnight, added H2O to quench the reaction, extracted with ethyl acetate (100 mL 3), the organic phase was washed with brine (30 mL 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-TLC (dichloromethane /MeOH = 5/1 ) to give 6 (off- white solid, 40 mg, yield 41 %). LCMS (m/z): 1 91 [M + H] ⁺;

(E)-4-(4-cyclohexylphenyl)-4-oxo-N-((1-phenylpiperidin-4-yl)methyl)but-2-enamide (A37)

The mixture of 7 (100 mg, 0.387 mmol), HOBt (70 mg, 0.51 8 mmol), dichloromethane (5 mL), THF (5 mL) was stirred at r.t for 10 min, then EDC-HCI (160 mg, 0.835 mmol) was added, further stirred for 10 min, then 6 (40 mg, 0.21 mmol) was added, stirred at r.t overnight, after completion, extracted with ethyl acetate (80 mL 3), the organic phase was washed with brine (50 mL 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1 /1 ) and prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A37 (light yellow solid, 45 mg, yield 50 %). LCMS (m/z): 431 [M + H] ⁺; ¹ H NMR (DMSO-afe, 400 MHz) : d 8.65 (t, J = 5.6 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 1 5.6 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.1 6-7.23 (m, 2 H), 7.02 (d, J = 15.2 Hz, 1 H),6.92 (d, J = 8.4 Hz, 2 H), 6.74 (t, J = 7.2 Hz, 1 H), 3.69 (d, J = 12.0 Hz, 2 H),3.15 9t, J = 6.4 Hz, 2 H), 2.59 (t, J = 12.0 Hz, 2 H), 1 .23-1 .48 (m, 15 H).

(E)-1 -(4-cyclohexylphenyl)-4-(4-methylpiperazin-1 -y l)but-2-ene-1 ,4-dione ( A7)

The mixture of 1 (240 mg, 0.929 mmol), HOBt (175 mg, 1 .30 mmol), dichloromethane (5 ml_),

THF (5 ml_) was stirred at r.t for 10 min, then EDC-HCI (380 mg, 1 .98 mmol) was added, further stirred for 10 min, then 1 -methylpiperazine (85 mg, 0.848 mmol) was added, stirred at r.t for 1 h, after completion, extracted with ethyl acetate (80 ml_ 3), the organic phase was washed with brine (50 ml_ 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A7 (off-white solid, 45 mg, yield 16 %). LCMS (m/z): 341 [M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 8.18 (s, 1 H), 7.96 (d, J = 8.0 Hz, 2 H), 7.76 (d, J = 15.2 Hz, 1 H), 7.43d (d+d, 3 H), 3.58 (s, 4 H), 2.61 (t, J = 1 0.8 Hz, 1 H), 2.33 ( 4 H), 2.21 (s, 3 H), 1 .69-1 .81 (m, 5 H), 1 .23-1 .48 (m, 5 H).

A38

(E)-N-cyclohexyl-4-(4-cyclohexylphenyl)-4-oxobut-2-enamide (A38)

The mixture of 1 (200 mg, 0.775 mmol), cyclohexanamine (72 mg, 0.727 mmol), HOBt (196 mg,

1 .45 mmol), EDCI (277 mg, 1 .45 mmol), dichloromethane (10 mL), THF (10 mL) was stirred at r.t overnight, after completion, the mixture was concentrated to remove the solvent, the residue was purified by flash column (petroleum ether/ethyl acetate = 5/1 ) to give A38 (white solid, 140 mg, yield 57%). LCMS (m/z): 340 [M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 7.97 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 14.8 Hz, 1 H), 6.99 (d, J = 14.8 Hz, 1 H), 6.04 (d, J = 8.0 Hz, 1 H), 3.92 (m, 1 H), 2.58 (m,

1 H), 1 .62-2.05 (m, 1 1 H), 1 .17-1 .49 (m, 10 H). A6

(E)-1 -(4-cyclohexylphenyl)-4-(4-o-tolylpiperazin-1 -yl)but-2-ene-1 ,4-dione ( A6)

The mixture of 1 (200 mg, 0.78 mmol), HOBt (21 1 mg, 1 .56 mmol), dichloromethane (6 ml_), THF (6 ml_) was stirred at r.t for 10 min, then EDC-HCI (298 mg, 1 .56 mmol) was added, further stirred for 10 min, then 2 (109 mg, 0.62 mmol) was added, stirred at r.t for 10 h, after completion, the mixture was concentrated to remove the solvent, the residue was purified by prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A6 (yellow solid, 58 mg, yield 18%). LCMS (m/z): 417 [M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 7.98 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 15.2 Hz, 1 H), 7.48 (d, J = 15.2 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.13-7.19 (m, 2 H), 6.96-7.03 (m, 2 H), 3.74 (s, 4 H), 2.86 (4 H), 2.62 (m, 1 H), 2.28 (s, 3 H), 1 .69-1 .82 (m, 5 H), 1 .26-1 .46 (m, 5 H).

A9

(E)-1-(4-cyclohexylphenyl)-4-(4-m-tolylpiperazin-1-yl)but-2-ene-1 ,4-dione (A9)

The mixture of 1 (200 mg, 0.774 mmol), HOBt (170 mg, 1 .26 mmol), dichloromethane (6 ml_),

THF (6 ml_) was stirred at r.t for 10 min, then EDC-HCI (400 mg, 2.09 mmol) was added, further stirred for 10 min, then 2 (99 mg, 0.562 mmol) was added, stirred at r.t for 6 h, after completion, the mixture was concentrated to remove the solvent, the residue was purified by prep-HPLC (C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A9 (light yellow solid, 75 mg, yield 32%). LCMS (m/z) : 417[M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 7.98 (d, J = 8.4 Hz, 2 H), 7.78 (d, J = 1 5.2 Hz, 1 H), 7.47 (d, J =

15.2 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.1 1 (t, J = 7.6 Hz, 1 H), 6.79 (s, 1 h), 6.76 (d, J = 8.4 Hz, 1 H), 6.64 (d, J = 7.2 Hz, 1 H), 3.73 (4 H), 3.1 6 (4 H), 2.61 (m, 1 H), 2.25 (s, 3 H), 1 .69-1 .81 (m, 5 H), 1 .36-1 .46 (m, 5 H).

A10

(E)-1 -(4-cyclohexylphenyl)-4-(4-p-tolylpiperazin-1 -yl)but-2-ene-1 ,4-dione ( A10)

The mixture of 1 (200 mg, 0.774 mmol), HOBt (200 mg, 1 .48 mmol), dichloromethane (6 ml_),

THF (6 ml_) was stirred at r.t for 10 min, then EDC-HCI (350 mg, 1 .83 mmol) was added, further stirred for 10 min, then 2 (1 00 mg, 0.567 mmol) was added, stirred at r.t overnight, after completion, the mixture was concentrated to remove the solvent, the residue was purified by prep-TLC (dichloromethane/MeOH = 20/1 ) and prep-HPLC(C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A10 (light yellow solid, 78 mg, yield 33%). LCMS (m/z): 417[M + H] ⁺; ¹ H NMR (DMSO-cfe, 400 MHz): d 7.98 (d, J = 8.4 Hz, 2 H), 7.78 (d, J = 1 5.2 Hz, 1 H), 7.48 (d, J = 1 5.2 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.05 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 3.73 (4 H), 3.1 1 (4 H), 2.62 (m, 1 H), 2.21 (s, 3 H), 1 .70-1 .81 (m, 5 H), 1 .23-1 .46 (m, 5 H).

A11

(E)-1 -(4-(3-bromophenyl)piperazin-1 -yl)-4-(4-cyclohexylphenyl)but-2-ene-1 ,4-dione (A11 )

The mixture of 1 (200 mg, 0.78 mmol), HOBt (150 mg, 1 .56 mmol), dichloromethane (6 ml_), THF (6 ml_) was stirred at r.t for 10 min, then EDC-HCI (300 mg, 1 .56 mmol) was added, further stirred for 10 min, then 2 (150 mg, 0.62 mmol) was added, stirred at r.t for 1 h, after completion, the mixture was concentrated to remove the solvent, the residue was purified by prep-HPLC(C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A11 (white solid, 41 mg, yield 1 1 %). LCMS (m/z): 481 [M +

H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 7.98 (d, J = 8.4 Hz, 2 H), 7.78 (d, J = 15.2 Hz, 1 H), 7.47 (d, J = 15.2 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.17 (t, J = 8.0 Hz, 1 H), 7.1 1 (s, 1 H), 6.94-6.98 (m, 2 H), 3.71 (4 H), 3.24 (4 H), 2.61 (m, 1 H), 1 .69-1 .82 (m, 5 H), 1 .36-1 .46 (m, 5 H).

A12

(E)-1 -(4-(4-bromophenyl)piperazin-1 -yl)-4-(4-cyclohexylphenyl)but-2-ene-1 ,4-dione (A12)

The mixture of 1 (200 mg, 0.774 mmol), HOBt (200 mg, 1 .48 mmol), dichloromethane (6 mL),

THF (6 mL) was stirred at r.t for 10 min, then EDC-HCI (410 mg, 2.14 mmol) was added, further stirred for 10 min, then 2 (1 10 mg, 0.456 mmol) was added, stirred at r.t overnight, after completion, the mixture was concentrated to remove the solvent, the residue was purified by prep-HPLC(C18 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A12 (light yellow solid, 50 mg, yield 23%). LCMS (m/z):

481 [M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 7.97 (d, J = 8.4 Hz, 2 H), 7.78 (d, J = 15.2 Hz, 1 H), 7.47 (d, J = 1 5.2 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.37 (t, J = 8.8 Hz, 2 H), 6.93 (d, J = 9.2 Hz, 2 H), 3.72 (4 H), 3.19 (4 H), 2.61 (m, 1 H), 1 .69-1 .82 (m, 5 H), 1 .22-1 .45 (m, 5 H). A2

(E)-1-(4-cyclohexylphenyl)-4-(4-(trifluoromethyl)piperidin-1-yl)but-2-ene-1 ,4-dione (A2)

The mixture of 1 (130 mg, 0.503 mmol), HOBt (72 mg, 0.533 mmol), dichloromethane (6 ml_),

THF (6 ml_) was stirred at r.t for 10 min, then EDC-HCI (193 mg, 1 .01 mmol) was added, further stirred for 10 min, then 2 (80 mg, 0.522 mmol) was added, stirred at r.t overnight, after completion, extracted with ethyl acetate (80 ml_ 2), the organic phase was washed with brine (50 ml_ 2), dried with Na2SC>4, filtered, removed the solvent, the residue was purified by prep-HPLC (C1 8 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A2 (light yellow solid, 30 mg, yield 15 %). LCMS (m/z):

394[M + H] ⁺; ¹ H NMR (DMSO-de, 400 MHz): d 7.98 (d, J = 8.8 Hz, 2 H), 7.94 (d, J = 15.2 Hz, 1 H), 7.48 (d, J = 1 5.2 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 2 H), 4.82 (d, J = 12.0 Hz, 1 H), , 4.1 8 (d, J = 14.4 Hz, 1 H), 3.15 (t, 1 H), 2.68(t, 1 H), 2.58 (t, 1 H), 2.32 (m, 1 H), 1 .75-2.01 (m, 7 H), 1 .25-1 .46 (m, 7 H).

A1

(£)- 1 -(4-cyclohexylphenyl)-4-(4-methylpiperidin-1 -yl)but-2-ene-1 ,4-dione (A1 )

The mixture of SM-1 (7550 mg, 29.228mmol), HOBt (5924 mg, 43.842 mmol) and

dichloromethane (30 ml_) was stirred at rt for 10 min, then added EDCI (1 1206 mg, 29.228 mmol) to the mixture, stirred at rt for 10 min, at last added SM-2 (2899 mg, 29.228 mmol) to the mixture and stirred at rt for 30 min, after completion, concentrated to remove solvents, extracted with ethyl acetate and washed by saturated brines for 2 times, combined organic layer and dried over Na2S04, concentrated and purified by silica gel (petroleum ethenethyl acetate = 10:1 ), further purified by pre-HPLC to get A1 as light yellow oil (1 .204 g) LCMS (m/z): 340.1 [M + H]⁺, 701 .2 [2M+Na]⁺. ¹ H NMR (400 MHz, DMSO) d 7.97 (d, J = 8 Hz, 2 H), 7.74 (d, J = 15.2 Hz, 1 H), 7.43 (m, 3 H), 4.43 (d, J = 13.2 Hz, 1 H), 3.98 (d, J = 13.6 Hz, 1 H ), 2.63 (t, J = 12.2 Hz, 1 H), 2.58-2.71 (m, 2 H), 1 .81 (d, J = 1 1 .2 Hz, 4 H), 1 .65-1 .73 (m, 4 H), 1 .23-1 .48 (m, 5H), 0.99-1 .08 (m, 2 H), 0.92 (d, J = 6 Hz, 3 H). A14

(£)-1-(4-cyclohexylphenyl)-4-(4-(pyridin-2-yl)piperazin-1-yl)but-2-ene-1 ,4-dione (A14)

The mixture of (£)-4-(4-cyclohexylphenyl)-4-oxobut-2-enoic acid (87 mg, 0.337 mmol), HOBt (62 mg, 0.459 mmol) and dichloromethane/THF=1 /1 (4 ml_) was stirred at rt for 10 min, then added EDCI (1 17 mg, 0.612 mmol) to the mixture, stirred at rt for 10 min, at last added 1 -(pyridin-2-yl)piperazine (50 mg, 0.306 mmol) to the mixture and stirred at rt for 16 h, after completion, concentrated to remove solvents, extracted with ethyl acetate and washed by saturated brines for 2 times, combined organic layer and dried over Na2SC>4, concentrated and purified by silica gel (dichloromethane:MeOH=20:1 ), further purified by pre-HPLC to get A14 as solid (10 mg, isolated yield 8%). LCMS (m/z): 404.1 [M + H]⁺, ¹ H NMR (400 MHz, DMSO) d 8.14 (d, J = 3.6 Hz, 1 H), 7.99 (d, J = 8 Hz, 2 H), 7.81 (d, J = 15.2 Hz, 1 H),

7.59-7.54 (m, 1 H), 7.50-7.42 (m, 3 H), 6.87 (d, J = 8.8 Hz, 1 H), 6.69-6.66 (m, 1 H), 3.72-3.68 (m, 4 H),

3.59-3.52 (m, 4 H), 2.65-2.59 (m, 1 H), 1 .82 (d, J = 1 1 .2 Hz, 4 H ), 1 .73 (d, J = 1 1 .2 Hz, 1 H), 1 .49-1 .23 (m,5 H).

A4

(E)-1 -(4-cyclohexylphenyl)-4-(4-(2-(trifluoromethyl)phenyl)piperazin-1 -yl)but-2-ene-1 ,4- dione (A4)

THF (6 ml_) was stirred at r.t for 10 min, then EDC-HCI (193 mg, 1 .01 mmol) was added, further stirred for 10 min, then 2 (120 mg, 0.521 mmol) was added, stirred at r.t overnight, after completion, extracted with ethyl acetate (80 ml_ 2), the organic phase was washed with brine (50 ml_ 2), dried with Na2S04, filtered, removed the solvent, the residue was purified by prep-HPLC (C1 8 column, CH3CN/H2O, containing 0.05% trifluoroacetic acid) to give A4 (off-white solid, 25 mg, yield 1 1 %). LCMS (m/z): 471 [M + H] ⁺; ¹ H NMR (DMSO-afe, 400 MHz): d 7.96-8.00 (d+d, 3 H), 7.66 (d, J = 7.6 Hz, 1 H), 7.50-7.56 (m, 2 H), 7.25-7.36 (m, 4 H), 3.89 (s, 2 H), 3.78 (t, J = 4.8 Hz, 2 H), 2.96 (4 H), 2.58 (t, 1 H), 1 .74-1 .88 (m, 6 H), 1 .24-1 .46 (m, 5 H). A3

ferf-butyl 4-(2,6-difluorophenyl)piperazine-1-carboxylate (3)

The mixture of 1 ,2,3-trifluorobenzene (1 .0 g, 7.57 mmol), ferf-butyl piperazine-1 -carboxylate (1 .410 g, 7.57 mmol) and CS2CO3 (4.933 g, 15.14 mmol) in NMP (20 ml_) was stirred at 150 ^SC for 6 hours after cooled down to rt, the mixture was diluted with ethyl acetate (100 ml_), washed with saturated brines (100 ml_ x 3), dried over Na2SC>4, concentrated and purified by column chromatography in silica gel (petroleum ethenethyl acetate = 5:1 ) to get 3 as solid (970 mg, isolated yield 43%). LCMS (m/z) : 243.0 [M-56 + H]⁺.

1 -(2,6-dif luorophenyl)piperazine (4)

To the solution of ferf-butyl 4-(2,6-difluorophenyl)piperazine-1 -carboxylate (54 mg, 0.1 81 mmol) in dichloromethane (5 ml_) was added trifluoroacetic acid (0.5 ml_), the mixture was stirred at rt for 2 hours and concentrated to leave the crude 4 as oil (54 mg, yield 99%), which was used directly for the next step. LCMS (m/z): 199.0 [M+ H]⁺.

(E)-1-(4-cyclohexylphenyl)-4-(4-(2,6-difluorophenyl)piperazin-1-yl)but-2-ene-1 ,4-dione (A3)

The mixture of (£)-4-(4-cyclohexylphenyl)-4-oxobut-2-enoic acid (70 mg, 0.272 mmol) and HOBt (55 mg, 0.408 mmol) in dichloromethane (5 mL) was stirred at rt for 10 min, and then EDCI (104 mg,

0.544 mmol) and DIPEA (0.5 mL) were added, the mixture was stirred at rt for 10 min, 1 -(2,6- difluorophenyl)piperazine (54 mg, 0.272 mmol) was added and the mixture was stirred at rt for 8 hours. The mixture was concentrated in vacuum, the residue was purified by pre-HPLC to get A3 as solid (10 mg, isolated yield 8%). LCMS (m/z): 439.0 [M + H]⁺, ¹ H NMR (400 MHz, DMSO) d 7.99 (d, J = 8.0 Hz, 2 H), 7.81 (d, J = 15.2 Hz, 1 H), 7.49-7.42 (m, 2 H), 7.13-7.01 (m, 1 H), 6.88 (t, J = 7.4 Hz, 1 H), 3.75 (s, 4 H), 3.09 (s, 4 H),2.61 (t, J = 9.8 Hz, 1 H), 1 .81 (d, J = 1 0.8 Hz, 4 H), 1 .73 (d, J = 12.8 Hz, 1 H), 1 .48-1 .23 (m, 7 H).

The following compound has also been prepared.

Example 2. SREBP Inhibition Data by Cell Viability and qRT-PCR Assays

Cell Viability Assay. Cells were treated for 72 hours in full serum in 96-well format with 5 increasing concentrations of compound; ATP production was assessed with Promega CellTiter-Glo reagent. Percentage (%) viability was calculated based on vehicle (DMSO) control wells. IC50s were calculated from the cell viability data using Prism unless noted otherwise. The IC50 data are listed in Table 1 below. The results are also illustrated in FIGs. 1 A and 1 B.

Quantitative Real-Time PCR Assay. Cells were treated in a 12-well format with a test compound in serum-free media for 24 hours. Approximate transcriptional IC50s were obtained from SCD1 , HMGCR levels normalized to b-actin and vehicle control. The IC50 data, if falling within the tested range, are listed in Table 1 below. The results are also illustrated in FIGs. 2A and 2B.

Table 1

^* indicates that Prism IC50 was ambiguous, and IC50 value was therefore determined by examining chart and data.

Compounds described herein may be tested in other cancer cell lines using assays known in the art or those described herein. For example, other cancer cell lines sensitive to the inhibition of

SREBP/KIX domain binding are described in lorio et al., Cell, 166, 740-754, 2016. Compounds useful in the invention are those which inhibit the SREBP/KIX domain binding. Example 3. Fluorescence Polarization Binding Assays

A peptide corresponding to amino acids 17-42 of the SREBP-1 a activation domain was FITC- or TAMRA-labeled at the N-terminus with an AHA linker (sequences with FITC- and TAMRA-AHA- GPCDLDAALLTDIEDMLNLINNQDSD were generated by Tufts University Core Facility). The peptide was solubilized in phosphate buffer (10.6 mM Na2HPC>4, 1 .93 mM NaH2PC>4, 0.5 mM EDTA, 0.01 % Nalsta, pH 7.6). The MED15 KIX domain was expressed as a His6-GST fusion protein and purified by affinity chromatography with Ni-NTA resin (Qiagen) and size exclusion chromatography (Sephadex 75, Pharmacia). The Kd for SREBP-1 a TAD binding to MED15 KIX was determined to be 36 nM and 2 mM with FITC and TAMRA tags, respectively, by fluorescence polarization (FP) assay. The CBP KIX domain was expressed as GST fusion protein and purified by affinity chromatography with Pierce Glutathione Agarose resin (ThermoFisher) and size exclusion chromatography (Sephadex 75, Pharmacia). The Kd for SREBP-1 a TAD binding to CBP KIX was determined to be 13 nM and 290 nM with FITC and TAMRA tags, respectively, by FP assay. Round bottom 384-well assay plates (Corning cat. no. #3575) were used to prepare 30 pL samples with 30 nM SREBP-1 a FITC-peptide or 30 nM SREBP-1 a TAMRA-peptide. GST-tagged MED15 KIX and CBP KIX were prepared with concentrations ranging from 0 to 300 mM. Compound IC50s were determined with GST-tagged MED15 KIX and CBP KIX held at 3 pM and 1 pM, respectively. The peptide concentration was always kept at 30 nM regardless of the fluorophor.

Compounds were titrated with a high precision HP D300 digital dispenser (Tecan Group, Maennersdorf, Switzerland) at concentrations ranging from 0 to 500 pM. FP titration curves were fitted with GraphPad Prisms (La Jolla, CA, USA) One site - total binding equation. Competition assay curves were fitted with R studios dose-response model. Fluorescence anisotropy was measured in duplicate using a Perkin Elmer EnVision plate reader fitted with fluorescein and BODIPY interference filters. The fluorescence polarization binding assay results for MED15 or CBP binding assay are provided in Table 2. Table 2

Example 4. Biological Tests

(1 ) Cell Titer Glo

Cells were seeded in 96 well plates as follows: U251 -MG cells were seeded in DMEM/F12 + 10% FBS at a density of 1 ,300 cells per well, RCC-JF cells were seeded in DMEM/F12 + 5% FBS at a density of 2,000 cells per well, and all other cell lines were plated to be in growth phase (-80% density) at the end of the assay. Cells were grown for - 24 hours before treatment. For 1 % LPDS (lipoprotein-deficient serum) treatment, media was removed and swapped with DMEM/F12 + 1 % LPDS. For full-serum treatment, media was not changed. For serum starve treatment (RCC-JF cells only), media was removed and swapped with DMEM/F12. SREBPi were added to indicated concentration in the same media. Cells were grown for 72 hours. After 72 hours, cell viability was measured using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega) and read with an Envision plate reader. Viability was normalized to DMSO vehicle control growth. The results of this assay are shown in FIGS. 4A, 5A, 1 1 A, 1 1 B, and 12. The IC50 values (mM) measured in FBS or LDPS for P32, X1 , and A1 are provided in Table 3.

Table 3

(2) CMT screening

Cell viability assays were carried out as described in the following publication:

Garnett, M. J., et al. (2012). "Systematic identification of genomic markers of drug sensitivity in cancer cells." Nature 483(7391 ): 570-575. The results of this assay are shown in FIG. 7.

(3) Apoptosis assay

U251 -MG cells were seeded in DMEM/F12 + 10% FBS in 96-well plates at a density of 5,000 cells per well and grown for 24 hours. Media was removed and swapped with DMEM/F12 + 1 % LPDS and SREBPi were added to indicated concentration. Cells were grown for 9 hours. After 9 hours, apoptosis was measured using a Caspase 3/7-Glo assay kit (Promega) and read with an Envision reader. Apoptosis was normalized to a DMSO vehicle control.

(3b) ccRCC Apoptosis assay with concurrent viability assay

RCC-JF cells were seeded in 96-well plates in DMEM/F12 + 5% FBS to a density of 4,000 cells per well. After ~24h, cells were treated with SREBPi at concentrations indicated. After 24 hours, cell viability was measured using a CellTiter-Glo Luminescent Cell Viability Assay kit and apoptosis was measured using a Caspase 3/7-Glo assay kit (Promega). Plates were read with an Envision reader and values normalized to a DMSO vehicle control. The results of this assay are shown in FIGS. 15A and 15B.

(4) Quantitative real-time PCR studies

Cells were seeded in 12-well poly-D-lysine coated plates as follows: U251 -MG cells were seeded in DMEM/F12 + 10% FBS at a density of 65,000 cells per well and RCC-JF cells were seeded in

DMEM/F12 + 5% FBS at a density of 100,000 cells per well. All other cells were seeded to be ~ 80% density at the end of the assay. After ~ 24 hours, media was removed, and cells were treated with SREBPi in DMEM/F12 + 1 % LPDS (for U251 -MG) or DMEM/F12 with no serum (RCC-JF) at

concentrations indicated. Cells were harvested in TRIzol (Thermo Fisher) or a RNeasy kit (Qiagen) after 20 hours, and RNA was prepared according to manufacturer’s instructions. The Transcriptor First Strand cDNA synthesis kit (Roche) was used to make cDNA for quantitative real-time PCR analysis and reactions with FastStart Universal SYBR Green Master (ROX) (Roche) were run on a Roche LightCycler 480. Transcript abundance was normalized to beta-actin or RPLP0 and DMSO (vehicle) control. The results of this assay are shown in FIGS. 4B, 5B, 13, and 14. (5) Transfection assays (U251 -MG cells)

U251 -MG cells were seeded in DMEM/F12 + 10% FBS in 96 well plates at a density of 5,000 cells per well and grown overnight. Media was removed and swapped to DMEM/F12 + 1 % LPDS. Cells were transfected with siRNA using lipofectamine RNAiMAX. After 72 hours viability was assessed with a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega) and apoptosis was measured using a Caspase 3/7-Glo assay kit (Promega); both were read with an Envision plate reader. cDNA was prepared for quantitative real-time PCR using a Cells-to-CT kit (Thermo Fisher). qRT-PCR reactions with FastStart Universal SYBR Green Master (ROX) (Roche) were run on a Roche LightCycler 480. Transcript abundance was normalized to RPLP0 and a non-targeting si control.

FIGS. 8A-8C.

U251 -MG cells were treated with SREBPi in DMEM/F12 + 1 % LPDS. After 20 hours, RNA was harvested using Qiagen RNeasy kit. cDNA made with Roche First Strand cDNA synthesis kit;

quantitative real-time PCR performed with SybrGreen reagent on a Roche Light Cycler 480. The results of this assay are shown in FIGS. 9A, 9B, 10A, and 10B.

(6) GBM models

1 x10⁵ MGG8 cells were stereotactically implanted into the right striatum of 7-week-old female nude mice. Mice were randomized and received treatments of DMSO (0.25% in PBS, 6 microliter), P32 (250 uM, 6 microliter), or X1 (250 uM, 6 microliter) infusions directly into the tumor on day 5 and day 10 post tumor implantation. Animals were followed for survival and euthanized when significant neurologiocal deterioration was noticed. P values were calculated using a log-rank test. For U251 -MG study, DMSO and A1 (500 uM, 6 uL) were used. The results of these assays are shown in FIGS. 6A and 6B.

(7) FASN-luciferase

For these assays, a !uciferase-expressing vector (FASN-Luc) containing a firefly luciferase open reading frame under the control of a minimal human fatty acid synthetase (FASN) promoter was used. Similar constructs under minimal promoters for CREB, LDLT, and SCD1 were used to test select compounds.

Duplicate 96-well plates (S!gma-A!drieh Cat No. P8616) were seeded at a density of 2.0x10³ HepG2 cells per well. One of the seeded plates was transfected with FASN-Luc using

Lipofectamine® 2000 (Invitrogen Cat No. 1 1668) 9-12 hours post-seeding and media on the plate was changed from Opti-MEM® (Invitrogen Cat No. 31985) back to 10% fetal bovine serum supplemented Dulbecco's modified Eag!e medium (DMEM; Invitrogen Cat No. 10566) approximately 6 hours post transfection. Around 24 hours after the plate was seeded (approximately 12 hours post-transfection and approximately 6 hours post-media change), compounds were added to both 96-well plates using identical plate layouts at select concentrations in triplicate in a total volume of 75 pL of DMEM with 1 % lipid- depleted serum per well. 12 hours post-small molecule addition, the transfected plate was assayed for !uciferase activity using the Dual Glo® Luciferase Assay System (Promega Cat No. E2940) and the duplicate un-transfected plate was assayed for cell viability using the Ce!!Titer Glo® Luminescent Ceil Viability Assay (Promega Cat No. G7572) The results of this assay are shown in FIGS. 3A and 3B. (8) Synergy and Rescue Studies

For all studies, cells were seeded in DMEM/F12 with full serum in 96-well plates and grown ~ 24 h prior to treatment, after which media was swapped to 1 % LPDS for low-serum experiments.

Compounds were added to wells to concentrations indicated in the same media. After 72 hours, cell viability was measured using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega) and read with an Envision plate reader. Viability was normalized to DMSO vehicle control growth. Bliss Synergy was calculated using Synergy Finder (https://synergyfinder.fimm.fi/).

(a) RCC cells were seeded in 5% FBS to the following densities: RCC-AB 5000 cells/well, RCC-FG2 5000 cells per well, RCC-JF 3750 cells per well. RCC-AB / P32 results are in FIGS. 16A and 16B. RCC- FG2 / P32 results are in FIGS. 17A and 17B. RCC-JF / P32 results are in FIGS. 18A and 18B. RCC-AB / X1 results are in FIGS. 19A and 19B. RCC-FG2 / X1 results are in FIGS. 20A and 20B. RCC-JF / X1 results are in FIGS. 21 A and 21 B.

(b) U251 -MG cells were seeded in 10% FBS to a density of 5,000 cells per well. After ~ 24 hours, media was swapped to DMEM/F12 + 1 % LPDS. Viability was assessed after 24 hours.

The results for erastin/P32 combination produced a synergy score of 32.34 and most synergistic area score of 38.73. The data were generated using Bliss method. The results are shown in FIGS. 22A-22C.

The results for erastin/X1 combination produced a synergy score of 12.49 and most synergistic area score of 15.22. The data were generated using Bliss method. The results are shown in FIGS. 23A- 23C.

(c) RCC-JF cells were seeded in 5% FBS to a density of 2,000 cells per well.

FIG. 24A is a chart assessing the synergy between 666-15 and P32 in FBS, max score was 18.8. FIG. 24B is a chart assessing the synergy between 666-15 and P32 in LPDS, max score was 6.2. FIG. 25A is a chart assessing the synergy between fatostatin and P32 in FBS, max score was 12,34. FIG.

25B is a chart assessing the synergy between fatostatin and P32 in LPDS, max score was 5.88. FIG.

26A is a chart assessing the synergy between A-485 and P32 in FBS, max score was 10.4. FIG. 26B is a chart assessing the synergy between A-485 and P32 in LPDS, max score was 8.52. FIG. 27A is a chart assessing the synergy between PF429242 and P32 in FBS, max score was 2.66. FIG. 27B is a chart assessing the synergy between PF429242 and P32 in LPDS, max score was 3.04.

FIG. 28A is a chart assessing the synergy between 666-15 and X1 in FBS, max score was 13.2. FIG. 28B is a chart assessing the synergy between 666-15 and X1 in LPDS, max score was 4.05. FIG. 29A is a chart assessing the synergy between fatostatin and X1 in FBS, max score was 1 1 .83. FIG. 29B is a chart assessing the synergy between fatostatin and X1 in LPDS, max score was 13.37. FIG. 30A is a chart assessing the synergy between A-485 and X1 in FBS, max score was 2.56. FIG. 30B is a chart assessing the synergy between A-485 and X1 in LPDS, max score was 0.98. FIG. 31 A is a chart assessing the synergy between PF429242 and X1 in FBS, max score was 1 .067. FIG. 31 B is a chart assessing the synergy between PF429242 and X1 in LPDS, max score was 4.64.

The compounds have the following structures:

erastin (d) U251 -MG cells were seeded in DMEM/F12 + 1 0% FBS to a density of 5,000 cells per well. After

~ 24 hours, media was swapped to DMEM/F12 + 1 % LPDS. SREBPi were added to concentrations indicated. Fatty Acid Supplement (FA; Sigma) was added at 1 :200. SyntheChol reagent (SC; Sigma) was added at 1 :500. Viability was assessed after 24 hours. The results of this assay are provided in FIGS. 32A and 32B. (9) Chromatin IP assays

ChIP was performed as described previously (Schmidt et al. , D. Schmidt, M.D. Wilson, C.

Spyrou, G.D. Brown, J. Hadfield, D.T. Odom ChIP-seq: using high-throughput sequencing to discover protein-DNA interactions Methods, 48 (2009), pp. 240-248). Briefly, U251 -MG cells were cultured in 10%FBS full medium until 95% confluency and then switched to 1 %LPDS medium with DMSO, 6 mM P32 or X1 for 16 hours, respectively. 10%FBS medium with DMSO was used as control. About 1 x10 7 cells were cross-linked with 1 % formaldehyde for 10 minutes only or 2 mM DSG crosslinker (CovaChem) at room temperature for 1 hour followed by secondary fixation with 1 % formaldehyde for 10 minutes. After neutralization with 0.125 M glycine and nuclear extraction, average length of genomic DNA was sonicated in lysis buffer with Q800R sonicator (QSonica) to get to -200-500 bp and soluble chromatin was incubated with 4 pg of antibody at 4°C overnight. The antibodies used in ChIP were: anti-MED1 (A300- 793A, Bethyl), anti-MED1 (sc-74475, Santa Cruz), anti- RPB1 CTD (2629S, Cell Signaling Technology) and anti-Rabbit IgG (ab171870, Abeam). Immunoprecipitated complexes were pulled down using 40 pi Dynabeads Protein G (Life Technologies) for each ChIP. Beads were washed with washing buffer 6 times to minimize the background. Protein-DNA complexes were then eluted and DNAfragments were purified. The purified DNA was subjected to qPCR directly to confirm target region enrichment. qPCR was conducted with Fast SYBR Green Master Mix (ThermoFisher) using QuantStudio 6 Flex Real-Time PCR System (ThermoFisher) according to the manufacturer’s instructions. Primer sets used in the assay are as follows: FASN promoter: Fw: 5’- CCAAGCTGTCAGCCCATGT-3’ Rv: 5’- CGTCTCTCTGGCTCCCTCTA-3’, SCD promoter: Fw: 5’- GGCAGAGGGAACAGCAG ATT -3’ Rv: 5’- GGCTTCTGTAAACTCCGGCT-3’, HMGCR promoter: Fw: 5’- TCGAACGGCTATTGGTTGGC-3’ Rv: 5’- ACGAACGGTCGCCTTAACAA-3’. The results are shown in FIGS. 33 and 34.

OTHER EMBODIMENTS

Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.

Other embodiments are in the claims.

Claims

WHAT IS CLAIMED IS:

1 . A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

each R¹ is independently optionally substituted C3-10 cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1-9 heterocyclyl, halogen, optionally substituted C1-6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and

R² is hydroxyl, optionally substituted C1-6 alkoxy, or -N(R³)2, wherein each R³ is independently H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1-6 alkyl, or optionally substituted C1-9 heterocyclyl C1-6 alkyl, or both R³, together with the atom to which they are attached, combine to form an optionally substituted C1-9 heterocyclyl ;

provided that the compound is not any one of the following compounds:

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein n is 1 .

3. The compound of claim 1 , wherein L is -CH=CH-

4. The compound of claim 3, wherein L is trans -CH=CH-

5. The compound of claim 1 , wherein the compound is of formula (IA):

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is of formula (IB):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein R² is -N(R³)2.

8. The compound of claim 1 , wherein R² is a group of formula:

wherein

X is CH or N; and

R⁴ is H, optionally substituted C1 -6 alkyl, optionally substituted cycloalkyl, optionally substituted Ce- i o aryl, or optionally substituted C1 -9 heteroaryl.

9. The compound of claim 8, wherein X is CH.

10. The compound of claim 8, wherein X is N.

1 1 . The compound of claim 8, wherein R⁴ is optionally substituted C6-10 aryl, optionally substituted C1-

6 alkyl, or optionally substituted cycloalkyl.

12. The compound of claim 8, wherein R⁴ is methyl or trifluoromethyl.

13. The compound of claim 8, wherein R⁴ is

14. The compound of claim 1 , wherein each R³ is independently H or optionally substituted C1-9 heterocyclyl C1 -6 alkyl.

15. The compound of claim 14, wherein R² is a group of formula:

wherein

one of X¹ and X² is CH2, and the remaining X¹ or X² is NR⁵ or O, wherein R⁵ is H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted Ce-io aryl, or optionally substituted Ce-io aryl C1-6 alkyl.

16. The compound of claim 15, wherein X¹ is CH2.

17. The compound of claim 15, wherein X² is CH2.

18. The compound of claim 15, wherein the remaining X¹ or X² is O.

19. The compound of claim 15, wherein the remaining X¹ or X² is NR⁵.

20. The compound of claim 19, wherein R⁵ is H, optionally substituted C1 -6 alkyl, optionally substituted C2-6 alkynyl, or optionally substituted Ce-io aryl C1 -6 alkyl.

21 . The compound of claim 1 , wherein R¹ is optionally substituted cycloalkyl, optionally substituted C1 -9 heterocyclyl, or optionally substituted C2-6 alkynyloxy.

22. The compound of claim 21 , wherein R¹ is optionally substituted cycloalkyl.

23. The compound of claim 21 , wherein R¹ is optionally substituted cyclohexyl.

24. A compound selected from the group consisting of:

pharmaceutically acceptable salts thereof

25. A compound of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R³ is optionally substituted Ce-io aryl C1-6 alkyl or optionally substituted C1-6 alkyl;

R^A is H or optionally substituted C1-6 alkyl;

R^B is optionally substituted Ce-io aryl, optionally substituted Ob-io aryl C1-6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1-9 heterocyclyl, or optionally substituted C1-9 heterocyclyl C1-6 alkyl; and R^c is H or optionally substituted C1-6 alkyl; or R^B and R^c combine to form an optionally substituted C1-9 heterocyclyl;

P5 P6

pharmaceutically acceptable salts thereof.

26. The compound of claim 25, wherein n is 1 .

27. The compound of claim 25, wherein Z is -SO2-.

28. The compound of claim 25, wherein the compound is of formula (IIA):

or a pharmaceutically acceptable salt thereof.

29. The compound of claim 25, wherein R³ is -(CH2)-R^D, wherein R^D is optionally substituted phenyl.

30. The compound of claim 28, wherein R^D is phenyl substituted at the para position with halogen or C1 -6 alkoxy.

31 . The compound of claim 25, wherein R¹ is -CONR^BR^c.

32. The compound of claim 25, wherein R^B is optionally substituted Ce-io aryl.

33. The compound of claim 25, wherein R^B is optionally substituted 6-membered heteroaryl.

34. The compound of claim 25, wherein R^c is H.

35. The compound of claim 25, wherein R² is bromo.

36. The compound of claim 25, wherein R² is chloro.

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

each R¹ is independently optionally substituted cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1-9 heterocyclyl, halogen, optionally substituted C1-6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and

R² is hydroxyl, optionally substituted C1-6 alkoxy, or -N(R³)2, wherein each R³ is independently H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1-6 alkyl, or optionally substituted C1 -9 heterocyclyl C1 -6 alkyl, or both R³, together with the atom to which they are attached, combine to form an optionally substituted C1-9 heterocyclyl.

38. The pharmaceutical composition of claim 37, wherein n is 1 .

39. The pharmaceutical composition of claim 37, wherein L is -CH=CH-

40. The pharmaceutical composition of claim 37, wherein L is trans -CH=CH-.

41 . The pharmaceutical composition of claim 37, wherein the compound is of formula (IA):

or a pharmaceutically acceptable salt thereof.

42. The pharmaceutical composition of claim 37, wherein the compound is of formula (IB):

or a pharmaceutically acceptable salt thereof.

43. The pharmaceutical composition of claim 37, wherein R² is -N(R³)2.

44. The pharmaceutical composition of claim 37, wherein R² is a group of formula:

wherein

X is CH or N; and

45. The pharmaceutical composition of claim 44, wherein X is CH.

46. The pharmaceutical composition of claim 44, wherein X is N.

47. The pharmaceutical composition of claim 44, wherein R⁴ is optionally substituted C6-10 aryl, optionally substituted C1-6 alkyl, or optionally substituted cycloalkyl.

48. The pharmaceutical composition of claim 44, wherein R⁴ is methyl or trifluoromethyl.

49. The pharmaceutical composition of claim 44, wherein R⁴ is

50. The pharmaceutical composition of claim 37, wherein each R³ is independently H or optionally substituted C1 -9 heterocyclyl C1 -6 alkyl.

51 . The pharmaceutical composition of claim 50, wherein R² is a group of formula:

wherein

52. The pharmaceutical composition of claim 51 , wherein X¹ is CH2.

53. The pharmaceutical composition of claim 51 , wherein X² is CH2.

54. The pharmaceutical composition of claim 51 , wherein the remaining X¹ or X² is O.

55. The pharmaceutical composition of claim 51 , wherein the remaining X¹ or X² is NR⁵.

56. The pharmaceutical composition of claim 55, wherein R⁵ is H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkynyl, or optionally substituted Ce-io aryl C1-6 alkyl.

57. The pharmaceutical composition of claim 37, wherein R¹ is optionally substituted cycloalkyl, optionally substituted C1-9 heterocyclyl, or optionally substituted C2-6 alkynyloxy.

58. The pharmaceutical composition of claim 57, wherein R¹ is optionally substituted cycloalkyl.

59. The pharmaceutical composition of claim 57, wherein R¹ is optionally substituted cyclohexyl.

60. The pharmaceutical composition of claim 37, wherein the compound is not a compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1-6 alkyl;

R^A is H or optionally substituted C1-6 alkyl; and

R^B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1 -6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1 -9 heterocyclyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl ; and R^c is H or optionally substituted C1 -6 alkyl; or R^B and R^c combine to form an optionally substituted C1 -9 heterocyclyl.

62. The pharmaceutical composition of claim 61 , wherein n is 1 .

63. The pharmaceutical composition of claim 61 , wherein Z is -SO2-.

64. The pharmaceutical composition of claim 61 , wherein the compound is of formula (IIA):

or a pharmaceutically acceptable salt thereof.

65. The pharmaceutical composition claim 61 , wherein R³ is -(CH2)-R^D, wherein R^D is optionally substituted phenyl.

66. The pharmaceutical composition of claim 65, wherein R^D is phenyl substituted at the para position with halogen or C1 -6 alkoxy.

67. The pharmaceutical composition of claim 61 , wherein R¹ is -CONR^BR^c.

68. The pharmaceutical composition of claim 61 , wherein R^B is optionally substituted Ob-io aryl.

69. The pharmaceutical composition of claim 61 , wherein R^B is optionally substituted 6-membered heteroaryl.

70. The pharmaceutical composition of claim 61 , wherein R^c is H.

71 . The pharmaceutical composition of claim 61 , wherein R² is halogen.

72. The pharmaceutical composition of claim 61 , wherein the compound is not a compound selected from the group consisting of:

pharmaceutically acceptable salts thereof

73. A method of treating cancer in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 36, the pharmaceutical composition of any one of claims 37 to 72, the compound of formula (I), or the compound of formula (II); wherein the compound of formula (I) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

each R¹ is independently optionally substituted cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1-9 heterocyclyl, halogen, optionally substituted C1-6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ob-io aryloxy; and

R² is hydroxyl, optionally substituted C1-6 alkoxy, or -N(R³)2, wherein each R³ is independently H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted C6-10 aryl C1-6 alkyl, or optionally substituted C1 -9 heterocyclyl C1 -6 alkyl, or both R³, together with the atom to which they are attached, combine to form an optionally substituted C1-9 heterocyclyl; and

wherein the compound of formula (II) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1-6 alkyl; and

74. The method of claim 73, wherein the cancer is melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer.

75. The method of claim 73, wherein the cancer is metastatic.

76. A method of treating a metabolic disorder in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 36, the pharmaceutical composition of any one of claims 37 to 72, a compound of formula (I), or a compound of formula (II);

wherein the compound of formula (I) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

each R¹ is independently optionally substituted cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1-9 heterocyclyl, halogen, optionally substituted C1-6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and R² is hydroxyl, optionally substituted C1-6 alkoxy, or -N(R³)2, wherein each R³ is independently H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1-6 alkyl, or optionally substituted C1 -9 heterocyclyl C1 -6 alkyl, or both R³, together with the atom to which they are attached, combine to form an optionally substituted C1-9 heterocyclyl ; and

wherein the compound of formula (II) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1-6 alkyl; and

77. The method of claim 76, wherein the metabolic disorder is nonalcoholic steatohepatitis or cardiovascular disease.

78. A method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 36, the pharmaceutical composition of any one of claims 37 to 72, a compound of formula (I), or a compound of formula (II) ;

wherein the compound of formula (I) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-; each R¹ is independently optionally substituted cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted C1-9 heterocyclyl, halogen, optionally substituted C1-6 alkoxy, optionally substituted C2-6 alkenyloxy, optionally substituted C2-6 alkynyloxy, or optionally substituted Ce-io aryloxy; and

R² is hydroxyl, optionally substituted C1-6 alkoxy, or -N(R³)2, wherein each R³ is independently H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted Ce-io aryl C1-6 alkyl, or optionally substituted C1 -9 heterocyclyl C1 -6 alkyl, or both R³, together with the atom to which they are attached, combine to form an optionally substituted C1-9 heterocyclyl ; and

wherein the compound of formula (II) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1-6 alkyl; and

79. The method of claim 73, wherein the compound or the pharmaceutical composition is administered enterally.

80. The method of claim 79, wherein the compound or the pharmaceutical composition is administered orally.

81 . The method of claim 73, wherein the compound or the pharmaceutical composition is administered parenterally.

82. The method of claim 81 , wherein the compound or the pharmaceutical composition is administered intramuscularly, intratumorally, intravenously, subcutaneously, buccally, sublingually, sublabially, by inhalation, intra-arterially, intraventricularly, intraspinally, intrathecally, intraorbitally, intracranially, or topically.

83. The method of claim 73, wherein the subject is a human.

84. The method of claim 73, wherein the method further comprises administering a fatty acid/cholesterol homeostatsis modulator.

85. The method of claim 73, wherein the method further comprises administering an inducer of ferroptotic cell death.

86. The method of claim 73, wherein the method further comprises administering 666-15, fatostatin, A-485, PF429242, erastin, or a pharmaceutically acceptable salt thereof.

87. A method of killing a cancer cell comprising contacting the cancer cell with the compound of any one of claims 1 to 36, a compound of formula (I), or a compound of formula (II);

wherein the compound of formula (I) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 1 , 2, 3, 4, or 5;

L is -CH2CH2- or -CH=CH-;

wherein the compound of formula (II) has the following structure:

or a pharmaceutically acceptable salt thereof,

wherein

n is 0, 1 , or 2;

Z is -SO2- or -S-;

R¹ is -COOR^A or -CONR^BR^c;

each R², when present, is independently halogen;

R^A is H or optionally substituted C1-6 alkyl; and R^B is optionally substituted Ce-io aryl, optionally substituted Ce-io aryl C1 -6 alkyl, optionally substituted 5-membered heteroaryl, optionally substituted bicyclic heteroaryl, optionally substituted C1 -9 heterocyclyl, or optionally substituted C1-9 heterocyclyl C1 -6 alkyl ; and R^c is H or optionally substituted C1 -6 alkyl; or R^B and R^c combine to form an optionally substituted C1 -9 heterocyclyl.

88. The method of claim 87, wherein cancer cell is a melanoma cell, glioblastoma cell, prostate cancer cell, non-small cell lung cancer cell, or kidney cancer cell.

89. The method of claim 87, wherein the cell is in a subject.

90. The method of claim 89, wherein the subject is human.

91 . The method of claim 87, wherein the method further comprises contacting the cancer cell with a fatty acid/cholesterol homeostatsis modulator.

92. The method of claim 87, wherein the method further comprises contacting the cancer cell with an inducer of ferroptotic cell death.

93. The method of claim 87, wherein the method further comprises contacting the cancer cell with 666-15, fatostatin, A-485, PF429242, or erastin.

94. An agent capable of binding the KIX domain of CBP or MED15 to inhibit the binding between SREBP1 and the KIX domain of MED15 or CBP, wherein the agent is not a compound of any one of the following structures:

pharmaceutically acceptable salts thereof.

95. The agent of claim 94, wherein the agent is a small molecule.

96. The agent of claim 95, wherein the agent is the compound of any one of claims 1 to 36.

97. The agent of claim 94, wherein the agent is an antigen-binding protein.

98. The agent of claim 97, wherein the antigen-binding protein is an antibody or an antigen-binding fragment thereof.

99. A method of inhibiting binding between SREBP1 and the KIX domain of MED15 or CBP, the method comprising contacting MED15 or CBP with the agent of claim 94.

100. The method of claim 99, wherein MED15 or CBP is in a cell.

101 . The method of claim 100, wherein the cell is in a subject in need of inhibition of the binding between SREBP1 and the KIX domain of MED15 or CBP.

102. The method of claim 101 , wherein the subject suffers from a cancer.

103. The method of claim 102, wherein the cancer is melanoma, glioblastoma, glioma, prostate cancer, breast cancer, non-small cell lung cancer, or kidney cancer.

104. The method of claim 101 , wherein the subject suffers from a metabolic disorder.

105. The method of claim 104, wherein the metabolic disorder is nonalcoholic steatohepatitis or a cardiovascular disease.