JP2018150292A - Cancer treatment - Google Patents

Abstract

To provide a novel therapeutic agent for blood cancer such as myeloma, lymphoma, leukemia and the like.
An active ingredient is 2- (3,5-difluoro-3′methoxybiphenyl-4-ylamino) nicotinic acid, which is a dihydroorotic acid dehydrogenase (DHODH) inhibitor, represented by the following formula: Drugs for the treatment of blood cancer.

[Selection] Figure 1A

Description

  The present disclosure relates to a method for treating hematological cancer by treatment comprising a DHODH inhibitor.

  Dihydroorotic acid dehydrogenase inhibitors (DHODH inhibitors) are believed to be useful in the treatment of rheumatoid arthritis. However, we have a DHODH inhibitor 2- (3,5-difluoro-3′methoxybiphenyl-4-ylamino) nicotinic acid (also known as ASLAN003) or a pharmaceutically acceptable salt thereof. Are considered useful in the treatment of blood disorders.

  Known DHODH inhibitors include leflunomide or teriflunomide.

  That is, in a first aspect, the present disclosure administers a therapeutically effective amount of a DHODH inhibitor 2- (3,5-difluoro-3′methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof. A method for treating a patient with blood cancer.

  In one embodiment, the hematological cancer is selected from myeloma, lymphoma, leukemia, chronic myeloproliferative disease, undefined monoclonal hypergammaglobulinemia, myelodysplastic syndrome and plasma exchange.

  In one embodiment, the myeloma is selected from myeloma, amyloidosis and plasmacytoma.

  In one embodiment, the lymphoma is anaplastic large cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, lymphoblast Selected from multiple lymphoma, MALT lymphoma, mantle cell lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, and Waldenstrom's macroglobulinemia The

  In one embodiment, the chronic myeloproliferative disorder is selected from essential thrombocythemia, chronic idiopathic myelofibrosis, and true primary erythrocytosis.

  In one embodiment, the leukemia is selected from hairy cell leukemia, acute lymphoblastic leukemia, and chronic lymphoblastic leukemia.

  In one embodiment, the hematological cancer treatment is a pan-HER inhibitor (R) -N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (4-methyl-4 , 5, -dihydro-oxazol-2-yl) -quinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof.

  In one embodiment, the DHODH inhibitor provides an anti-cancer effect through induction of p53.

  In one embodiment, the DHODH inhibitor is administered orally, for example once a day.

  In one embodiment, the pan-HER inhibitor is administered parenterally.

  In one embodiment, the pan-HER inhibitor is administered orally, such as every other day.

  In one embodiment, each dose of pan-HER inhibitor is in the range of 100-900 mg, for example, each dose is in the range of 300-500 mg.

  Also, 2- (3,5-difluoro-3′methoxybiphenyl-4-ylamino) nicotinic acid or a pharmacological agent thereof for use in the treatment of blood cancer, particularly blood cancer disclosed herein. An acceptable salt is provided.

  Also, 2- (3,5-difluoro-3′methoxybiphenyl-4-ylamino) nicotinic acid for use in the manufacture of a medicament for the treatment of blood cancer, particularly blood cancer disclosed herein. Or a pharmaceutically acceptable salt thereof.

  The present disclosure also provides pan-HER inhibitors (eg, (R) -N4- [3-chloro-4-) for use in the treatment of hematological cancers, particularly the hematological cancers disclosed herein. (Thiazol-2-ylmethoxy) -phenyl] -N6- (4-methyl-4,5, -dihydro-oxazol-2-yl) -quinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof) and DHODH inhibition It extends to combination therapy including the agent 2- (3,5-difluoro-3′methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof.

  In a further aspect, 2- (3,5-difluoro-3′methoxybiphenyl-4, which is a DHODH inhibitor, in the manufacture of a combination therapy for the treatment of hematological cancers, particularly the hematological cancers disclosed herein. -Uses of -ylamino) nicotinic acid or pharmaceutically acceptable salts are provided.

  It is also a pan-HER inhibitor (e.g., R) -N4- [3-chloro-4-] in the manufacture of combination therapies for the treatment of blood cancers, particularly blood cancers disclosed herein. (Thiazol-2-ylmethoxy) -phenyl] -N6- (4-methyl-4,5, -dihydro-oxazol-2-yl) -quinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof) and DHODH inhibition Use of the agent 2- (3,5-difluoro-3′methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt is provided.

  In one embodiment, the treatment of the present disclosure comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 months or longer.

  (R) -N4- [3-Chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (4-methyl-4,5, -dihydro-oxazol-2-yl) -quinazoline-4,6- The diamine is also known as Varlitinib.

  In one embodiment, valritinib is administered in one cycle of 28 days. In one embodiment, administration of the balritinib component therapy is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 months or longer.

The disclosure is further elaborated in the following paragraphs.

1. A method of treating hematological cancer comprising administering a therapeutically effective amount of a DHODH inhibitor 2- (3,5-difluoro-3'methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof.

2. The hematological cancer is selected from myeloma, lymphoma, leukemia, chronic myeloproliferative disorder, undefined monoclonal hypergammaglobulinemia, myelodysplastic syndrome, plasma exchange amyloidosis and plasmacytoma The treatment according to paragraph 1.

3. The treatment according to paragraph 2, wherein the blood cancer is myeloma.

4). The treatment according to paragraph 2 or 3, wherein the blood cancer is lymphoma.

5. The treatment according to paragraph 4, wherein the lymphoma is selected from Hodgkin lymphoma and non-Hodgkin lymphoma.

6). Lymphoma is anaplastic large cell lymphoma, hemangioimmunoblastic lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, blastic NK cell lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, diffuse large cell Type B cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, 6. The method of any one of paragraphs 2-5, independently selected from Waldenstrom's macroglobulinemia and combinations thereof.

7). The treatment according to any one of paragraphs 2 to 6, wherein the blood cancer is a chronic myeloproliferative disease.

8). The treatment according to any one of paragraphs 2-7, wherein the chronic myeloproliferative disorder is selected from essential thrombocythemia, chronic idiopathic myelofibrosis, and true primary erythrocytosis.

9. The treatment according to any one of paragraphs 2 to 8, wherein the blood cancer is leukemia.

10. In paragraph 9, the leukemia is independently selected from AML (acute myeloid leukemia), ALL (acute lymphoblastic leukemia), CML (chronic myeloid leukemia) and CLL (chronic lymphocytic leukemia) and combinations thereof The described treatment.

11. 10. The method of paragraph 8 or 9, wherein the leukemia is selected from hair cell leukemia, acute lymphoblastic leukemia, and chronic lymphoblastic leukemia.

12 Leukemia is acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, hairy cell leukemia, T cell prolymphocytic leukemia, large granular lymphocytic leukemia, adult T cell Paragraph 9 independently selected from leukemia, clonal eosinophilia, T-cell granular leukemia, NK cell leukemia, adult T cell leukemia and combinations thereof, The treatment method as described in any one of -11.

13. The method of paragraph 12, wherein the leukemia is AML.

14 The method of paragraph 12, wherein the leukemia is ALL.

15. The method of paragraph 12, wherein the leukemia is CML.

16. The method of paragraph 12, wherein the leukemia is CLL.

17. The treatment according to any one of paragraphs 1-16, wherein a DHODH inhibitor is used in combination therapy with a second treatment.

18. The treatment according to paragraph 16, wherein the second treatment is an inhibitor of DNA repair.

19. 19. The method of paragraph 17 or 18, wherein the inhibitor is a small molecule therapy.

20. 20. The method of paragraph 18 or 19, wherein the inhibitor mechanism is via a base excision repair pathway.

21. 21. The method of paragraph 20, wherein the inhibitor target is independently selected from APE1, Polβ, FEN1, and PARP.

22. The inhibitor is also TRC102, (2E) -2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl) methylene] -undecanoic acid [E3330 NCS-667715 and NSC-124854, 8-oxoguanine, Tanespimycin, Luminespib, Alvespimycin, Ganetespib, Letaspimycin, 6-amino-8-[(6-iodo-1,3 -Benzodioxol-5-yl) thio] -N- (1-methylethyl) -9H-purine-9-propanamine (PU-H71), 4- [2-carbamoyl-5- [6,6- Dimethyl-4-oxo-3- (trifluoromethyl) -5,7-dihydroindazol-1-yl] anilino] cyclohexyl] 2-aminoacete (SNX-5422), Luminespib (resorcyinylic), 2- (2-ethyl-3,5-dihydroxy-6- (3-methoxy-4- (2-morpholinoethoxy) benzoyl) phenyl) -N , N-bis (2-methoxyethyl) acetamide (KW-2478), AT13387, 5,6-bis ((E) -benzylideneamino) -2-thioxo-2,3-dihydropyrimidin-4 (1H) -one (SCR7) and the treatment according to paragraph 20 or 21, selected from a combination of two or more thereof.

23. 23. The method of any one of paragraphs 20-22, wherein the inhibitor is a PARP inhibitor such as a PARP-1 inhibitor and / or a PARP-2 inhibitor.

24. The treatment according to paragraph 23, wherein the PARP inhibitor is independently selected from olaparib, lucaparib, nilaparib, iniparib, tarazoparib, beliparib, CEP9722, E7016, BGB-290, AZD-2461, 3-aminobenzamide and combinations thereof Law.

25. 25. The method of any one of paragraphs 18-24, wherein the inhibitor mechanism is via a mismatch repair pathway.

26. 26. The method of any one of paragraphs 18-25, wherein the inhibitor mechanism is via the nucleotide excision pathway.

27. 27. The method of paragraph 26, wherein the inhibitor is independently selected from 7-hydroxystaurosporine [UCN-01], trabectedin, MCI13E, NERI01 and combinations of two or more thereof.

28. 28. The method of any one of paragraphs 18-27, wherein the inhibitor mechanism is via a double-strand break repair pathway.

29. 29. The method of paragraph 28, wherein the inhibitor mechanism is via a non-homologous end joining pathway.

30. 30. The method of paragraph 28 or 29, wherein the inhibitor is via a homologous recombination pathway.

31. 31. The method of any one of paragraphs 17-30, wherein the treatment is a topoisomerase inhibitor, such as a topoisomerase I and / or II inhibitor.

32. The treatment according to paragraph 31, wherein the topoisomerase inhibitor is independently selected from irinotecan, topotecan, camptothecin, lamellarin D and combinations thereof.

33. Topoisomerase inhibitors are etoposide (VP-16), teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, 3-hydroxy-2-[(1R) -6-isopropenyl-3-methyl- 33. The method of paragraph 31 or 32, independently selected from cyclohex-2-en-1-yl] -5-pentyl-1,4-benzoquinone (HU-331) and combinations thereof.

34. Hematological cancer treatment is a pan-HER inhibitor such as (R) -N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (4-methyl-4,5, -dihydro- 34. The method of any one of paragraphs 1-33, further comprising oxazol-2-yl) -quinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof.

35. 35. The method of paragraph 34, wherein the pan-HER inhibitor is administered parenterally.

36. 35. The method of paragraph 34, wherein the pan-HER inhibitor is administered orally.

37. 38. The method of paragraph 36, wherein the pan-HER inhibitor is administered every other day.

38. 38. The method of paragraph 36 or 37, wherein each dose of pan-HER inhibitor is in the range of 100 to 900 mg, for example 200, 300, 400, 500, 600, 700, 800 mg.

39. 39. The method of paragraph 38, wherein each dose is in the range of 300-500 mg.

40. 40. The method of any one of paragraphs 1 to 39, wherein the DHODH inhibitor provides an anti-cancer effect via induction of p53.

41. 41. The method of any one of paragraphs 1-40, wherein the DHODH inhibitor is administered orally, for example, once a day.

42. 2- (3,5-Difluoro-3'methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof for use in the treatment of blood cancer.

43. Pan-HER inhibitors (eg (R) -N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (4-methyl-4) for use in the treatment of blood cancer , 5, -dihydro-oxazol-2-yl) -quinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof) and 2- (3,5-difluoro-3′methoxybiphenyl-4) which is a DHODH inhibitor -Ileamino) combination therapy comprising nicotinic acid or a pharmaceutically acceptable salt.

44. 2- (3,5-difluoro-3′methoxybiphenyl-4-ylamino), a DHODH inhibitor, in the manufacture of a treatment for the treatment of blood cancer, in particular the blood cancer disclosed herein Use of nicotinic acid or a pharmaceutically acceptable salt.

45. HER inhibitors (e.g., (R) -N4- [3-chloro-4- (thiazol-2-ylmethoxy) in the manufacture of combination therapies for the treatment of blood cancers, particularly blood cancers disclosed herein. ) -Phenyl] -N6- (4-methyl-4,5, -dihydro-oxazol-2-yl) -quinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof) and a DHODH inhibitor Use of (3,5-difluoro-3'methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt.

  The present disclosure also extends to the use of the DHODH inhibitor according to any one of paragraphs 1 to 45 for use in the treatment of blood cancer, in particular blood cancer as described herein.

  The disclosure further provides the use of a DHODH inhibitor according to any one of paragraphs 1 to 45 in the manufacture of a medicament for the treatment of blood cancer, in particular blood cancer as described herein. .

  DHODH is an important enzyme in the production of uridine, a central component in cells. Without wishing to be bound by theory, DHODH inhibitors may be able to upregulate p53-dependent apoptosis. Increased expression of p53 (which leads to cell cycle arrest and can lead to apoptosis at higher p53 levels), after sensing the level of intracellular uridine, stabilizes p53 and increases its concentration It is likely to occur through a mechanism that promotes the reaction.

  Furthermore, the present inventors have found that a DHODH inhibitor 2- (3,5-difluoro-3′methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof is capable of cancer cells via apoptosis. It has been shown that it is particularly advantageous for use in the treatment of blood cancer because it does not involve cell death due to necrosis.

  Necrosis is a form of cell injury that results in premature death of cells in living tissue due to autolysis (ie, destruction of the cells by the action of their own enzymes). Necrosis is caused by extra-cellular or extra-tissue factors such as infection, toxins, or trauma that lead to uncontrolled digestion of cellular components. In contrast, apoptosis is spontaneous and responsible for programmed and targeted cell death.

  Apoptosis often has a beneficial effect on the organism, but necrosis is most often damaging to surrounding tissues. Furthermore, necrotic cell death does not follow the apoptotic signaling pathway, and various receptors are activated, leading to loss of cell membrane integrity and uncontrolled release of products into the extracellular space due to cell death.

  This causes an inflammatory response in the surrounding tissues, attracting leukocytes and nearby phagocytic cells that remove dead cells by phagocytosis. However, pathogen-damaging substances released by leukocytes cause incidental damage to surrounding tissues. This excessive incidental damage inhibits the healing process. That is, untreated necrosis leads to the development of degrading dead tissue and cell debris at or near the site of cell death. A typical example is gangrene. For this reason, surgical removal of necrotic tissue (a procedure known as necrotic tissue resection) is often required.

  Thus, the ability to treat hematological cancer with a DHODH inhibitor that causes apoptotic cell death will result in fewer side effects and better overall outcome.

  DHODH is an important enzyme in the production of uridine, a central component in cells. Without wishing to be bound by theory, DHODH inhibitors may be able to upregulate p53-dependent apoptosis. Increased expression of p53 (which leads to cell cycle arrest and can lead to apoptosis at higher p53 levels), after sensing the level of intracellular uridine, stabilizes p53 and increases its concentration It is likely to occur through a mechanism that indicates the reaction.

  The following disease definitions are based on common terminology used by those skilled in the art. The definitions given below are not mutually exclusive and some specific states are included in more than one category.

  Hematological cancer, as used herein, refers to hematological cancers such as leukemia, lymphoma and myeloma.

Leukemia As used herein, leukemia is a group of cancers that often begins in the bone marrow and produces abnormally high levels of leucocytes (also known as white blood cells). Point to.

  There are four main types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML).

Leukemia can also be classified as:
Lymphocytic leukemia that occurs in cells that mature into lymphocytes (white blood cells) and myeloid leukemia that occurs in cells where cancers mature into erythrocytes (red blood cells).

  More specifically, leukemia includes acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, ciliary cell leukemia, T cell prolymphocytic leukemia, large granules Includes lymphocytic leukemia, adult T-cell leukemia and clonal eosinophilia.

Myeloma As used herein, myeloma includes multiple myeloma and solitary myeloma.

  Multiple myeloma is a plasma cell cancer that causes a plasma cell to form a tumor. It is often called multiple myeloma because it is found in multiple places in the body. If the cancer is concentrated in only one place, it is known as solitary myeloma.

  In common usage, the term myeloma is used to refer to multiple myeloma.

  Myeloma and myeloid leukemia have many commonalities. However, different cells are involved, and as described above, myeloma affects plasma cells, while myeloid leukemia affects myeloid cells. But both cancers start in the bone marrow.

  Some patients with myeloma develop acute myeloid leukemia.

Lymphoma Lymphoma, as used herein, refers to cancerous lymphocytes. Lymphomas mainly include Hodgkin lymphoma and non-Hodgkin lymphoma. However, the World Health Organism includes myeloma and immunoproliferative disorders in a common lymphoma class.

  Subtypes of lymphoma include Hodgkin lymphoma, non-Hodgkin lymphoma, mature B cell tumor, mature T cell tumor, mature NK cell tumor, and immunodeficiency related lymphoproliferative disease.

Chronic myeloproliferative disease Chronic myeloproliferative disease, as used herein, refers to a cancer in which abnormal red blood cells, white blood cells or platelets are made excessively by the bone marrow and accumulate in the blood. The type of myeloproliferative disorder is based on whether excess red blood cells, white blood cells, or platelets are being made. Sometimes the body makes two or more types of blood cells in excess, but usually one type of blood cell is affected more than the other.

  There are at least 6 types of chronic myeloproliferative diseases: chronic myelogenous leukemia (CML), polycythemia vera, primary myelofibrosis (also called chronic idiopathic myelofibrosis), instinct thrombocythemia, chronic Neutrophilic leukemia, and chronic eosinophilic leukemia. Chronic myeloproliferative disease can be acute leukemia, where so many abnormal white blood cells are made.

Myelodysplastic syndrome Myelodysplastic syndrome is a group of cancers in which immature blood cells in the bone marrow do not mature. The syndrome includes chronic myelomonocytic leukemia (CMML).

Unconfirmed monoclonal hypergammaglobulinemia (MGUS)
In unspecified monoclonal hypergammaglobulinemia, abnormal proteins produced by plasma cells, known as monoclonal proteins or M proteins, are present in the blood. The condition is benign, but some patients may be a precursor of hematological cancer.

Plasmacytoma Plasmacytoma is a plasma cell tumor that forms a tumor when plasma cells become cancerous and grow out of control

  Plasmacytomas not only infiltrate the hard part outside the bone, but also lock out normal cells in the bone marrow and then spread into large bone cavities in the body. Plasmacytoma in the bone can cause pain or fracture. Bone plasmacytoma often becomes multiple myeloma. If only one tumor forms, it is called a solitary plasmacytoma. If multiple small tumors are formed, the disease is multiple myeloma. Plasmacytoma can also invade soft tissues in the body. Plasmacytoma in soft tissue can continue to invade nearby areas and cause pain in the pharynx, tonsils or sinus sinus.

Amyloidosis Amyloidosis is a group of diseases. As used herein, however, amyloidosis generally refers to AL amyloidosis (formerly “primary systemic amyloidosis”), generally in the context of blood cancer. Although AL may be present even in the absence of blood cancer, in one embodiment, the present disclosure does not consider this aspect.

  In AL amyloidosis, the amyloidogenic protein is derived from the light chain component of an immunoglobulin. These light chains are produced by abnormal plasma cells or B cells that are normally present in the bone marrow.

  The underlying bone marrow disorder that gives rise to abnormal cells is, for example, undefined monoclonal hypergammaglobulinemia, most often very fine.

  In some cases, the underlying bone marrow disorder is multiple myeloma.

  Myeloma patients have or may develop AL amyloidosis, but patients with AL amyloidosis (without myeloma at the time of examination) rarely progress to terminal myeloma.

  AL amyloidosis can be caused by an abnormal light chain produced by lymphoma or chronic lymphocytic leukemia (CLL).

  For example, the use of a combination therapy where the second treatment is an inhibitor of DNA repair and / or a pan-HER inhibitor specifically “attacks” cancer cells by more than one mechanism using the combination therapy. This may be particularly advantageous in minimizing the ability to resist treatment of cancer.

  In one embodiment, a DHODH inhibitor of the present disclosure is used in combination therapy including chemotherapy, particularly the chemotherapy described herein.

  That is, a method is provided for treating a patient comprising administering a therapeutically effective amount of at least an inhibitor of HER2 and a therapeutically effective amount of a DHODH inhibitor.

  In one embodiment, the pan-HER inhibitor is an inhibitor of at least two HER receptors. In one embodiment, at least one of the HER receptors that are inhibited is HER2.

  In one embodiment, the pan-HER inhibitor is an organic chemical molecule having a molecular weight of, for example, 500 or less.

  In one embodiment, the pan-HER inhibitor has the molecular formula of formula (I) (disclosed in WO 2005/016346, fully incorporated herein by reference):

(I)

Wherein A is attached to at least one of the carbons in the 5, 6, 7 or 8 position of the bicyclic ring, and the bicyclic ring is 0, 1 or 2 independent R ³ groups. Has been replaced;

  X is N, CH, CF or C-CN;

  A is Q or Z;

  Q is

Is;

R ¹ is a substituted or unsubstituted, monocyclic or bicyclic, aryl or heteroaryl moiety;

R ² is H or substituted or unsubstituted C _1-8 alkyl, allyl, substituted benzyl;

R ³ is hydrogen, halogen, cyano, nitro, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl , arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl, _{^{heterocyclylalkyl, -NR 4 SO 2 R 5,}} -SO 2 NR 6 R 4, -C (O) R 6, -C (O) ^{OR 6, -OC (O) R} 6, -NR 4 C (O) OR 5, -NR 4 C (O) R 6, -C (O) NR 4 R 6, -NR 4 R 6, -NR 4 ^{C (O) NR 4 R 6} , -OR 6, -S (O) R 5, a _-SO 2 ^{R 5} or SR ^6,, said alkyl, alkenyl, alkynyl, cycloalkyl, Black cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl, and heterocyclylalkyl, oxo, _halogen, C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 -C _{10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl alkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, _{^{azido, -NR 4 SO 2 R 5,}} -SO 2 NR 6 ^{R 4, -C (O) R} 6, -C (O) OR 6, -OC (O) R 6, -NR 4 C (O) OR 5, -NR 4 C (O) CR 6, -C ( ^{O) NR 4 R 6, -NR} 4 R 6, -NR 4 C (O) NR 4 R 6, NR 4 C (NCN) NR 1 independently selected from the group consisting of ⁴ R ⁶ , —OR ⁶ , —S (O) R ⁵ , —SO ₂ R ⁵ , aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl. Optionally substituted with ~ 5 groups;

R ¹⁰ is hydrogen, halogen, cyano, nitro, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, partially unsaturated heterocyclyl, —NR ⁴ SO ₂ R ⁵ , —SO ₂ NR ⁶ R ⁴ , —C (O) R ⁶ , —C (O) ^{OR 6, -OC (O) R} 6, -NR 4 C (O) OR 5, -NR 4 C (O) R 6, -C (O) NR 4 R 6, -NR 4 R 6, -NR 4 ^{C (O) NR 4 R 6} , -OR 6, -S (O) R 5, a _-SO 2 ^{R 5} or SR ^6,, said alkyl, alkenyl, alkynyl, cycloalkyl Aryl, heteroaryl, heterocyclyl or partially unsaturated heterocyclyl, oxo, _halogen, C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10} cycloalkyl, _{C 3} - C ₁₀ cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, _{^{azido, -NR 4 SO2R 5, -SO 2}} NR 6 R 4, -C (O) R 6, -C (O) ^{OR 6, -OC (O) R} 6, -NR 4 C (O) OR 5, -NR 4 C (O) CR 6, -C (O) NR 4 R 6, -NR 4 R 6, -NR 4 ^{C (O) NR 4 R 6} , -NR 4 C (NCN) NR 4 R 6, -OR 6, -S (O) R 5, -SO 2 R 5, aryl, arylalkyl, f Roariru, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with 1-5 groups independently selected from the group consisting of heterocyclylalkyl, g is 1-3, each R ¹⁰ is the same May or may not be;

Alternatively, one or more of the R ¹⁰ groups are selected from the group consisting of O, S, SO, SO ₂ and NR ⁶ independently of each other, together with the atoms to which they are attached. A 3-10 membered cycloalkyl ring or heterocycloalkyl ring which may contain one or more additional heteroatoms may be completed, each ring carbon being halogen, C ₁ -C ₁₀ alkyl , _C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl alkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl ^{, oR 8, NR 6 R 8} , SR 6, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and Optionally substituted with 1 to 3 groups independently selected from the group consisting of terocyclylalkyl, provided that said ring contains two adjacent O atoms or two adjacent S atoms Without;

  Z is

And

Where R ⁶ = H, Z further includes:

Z includes one or more R ⁸ or R ⁹ groups, and the R ⁸ and R ⁹ groups may be bonded to the same or different atoms;

W and V are independently selected from the group consisting of CR ⁷ R ⁸ , CR ⁸ R ⁹ , O, NR ⁶ , S, SO, and SO ₂ ;

Y is selected from the group consisting of S, SO, SO ₂ , CR ⁷ CR ⁸ , and CR ⁸ R ⁹ , but if desired, when W is O, NR ⁶ , S, SO, or SO ₂ , V Is CR ⁸ R ⁹ and when V is O, NR ⁶ , S, SO, or SO ₂ , W and Y are each CR ⁸ R ⁹ ;

R ⁴ is H or C _1-6 alkyl;

R ⁵ is trifluoromethyl, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, or a partially unsaturated heterocyclic ring, , cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl, and heterocyclylalkyl, oxo, _halogen, C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 -C _{10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl alkyl, cyano, ^{nitro, OR 6, NR 4 R 6} , SR 6, trifluoromethyl, difluoromethoxy, trifluoromethoxy, A De, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted with 1-5 groups independently selected from the group consisting of heterocyclylalkyl;

R ⁶ , R ⁸ and R ⁹ are hydrogen, trifluoromethyl, C ₁ -C ₁₀ alkyl, (CH ₂ ) _0-4 C ₃ -C ₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, Independently selected from the group consisting of heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl, wherein said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, partially unsaturated heterocyclyl, and heterocyclylalkyl are oxo, halogen, C ₁ -C _{10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl alkyl, cyano, ^{nitro, OR 6, NR 6 R 8} , SR ^6. Trifluorome Substituted with 1 to 5 groups independently selected from the group consisting of til, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl May be;

R ⁷ is hydrogen, halogen, cyano, nitro, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, partially unsaturated heterocycle, —NR ⁴ SO ₂ R ⁵ , —SO ₂ NR ⁶ R ⁴ , —C (O) R ⁶ , —C (O ^{) OR 6, -OC (O)} R 6, -NR 4 C (O) OR 5, -NR 4 C (O) R 6, -C (O) NR 4 R 6, -NR 4 R 6, -NR ^{4 C (O) NR 4 R} 6, -OR 6, -S (O) R 5, a _-SO 2 ^{R 5} or SR ^6,, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl Heteroarylheterocyclyl, and partially unsaturated heterocyclyl, oxo, _halogen, C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl Alkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ⁴ SO ₂ R ⁵ , —SO ₂ NR ⁶ R ⁴ , —C (O) R ⁶ , —C (O) OR ⁶ , —OC (O) R ⁶ , —NR ⁴ C (O) OR ⁵ , —NR ⁴ C (O) CR ⁶ , —C (O) NR ⁴ R ⁶ , —NR ⁴ R ⁶ , —NR ⁴ C (O) NR ⁴ R ⁶ , —NR ⁴ C (NCN) NR ⁴ R ⁶ , —OR ⁶ , —S (O) R ⁵ , —SO ₂ R ⁵ , aryl, arylalkyl, heteroaryl Optionally substituted with 1 to 5 groups independently selected from the group consisting of heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl;

Alternatively, R ⁴ and R ⁶ are independently of each other, together with the atoms to which they are attached, one or more additional selected from the group consisting of O, S, SO, SO ₂ and NR ⁶ Of 3 to 10 membered cycloalkyl ring or heterocycloalkyl ring which may contain a heteroatom, each ring carbon may be halogen, C ₁ -C ₁₀ alkyl, C ₂ -C _{10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl alkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, ^aryl, OR 8, NR ⁶ R ^8, SR ^6, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl Contact Optionally substituted with 1 to 3 groups independently selected from the group consisting of heterocyclylalkyl, provided that said ring contains two adjacent O atoms or two adjacent S atoms Without;

Alternatively, R ⁶ and R ⁸ are independently of each other, together with the atoms to which they are attached, one or more additional selected from the group consisting of O, S, SO, SO ₂ and NR ⁶ Of 3 to 10 membered cycloalkyl ring or heterocycloalkyl ring which may contain a heteroatom, each ring carbon may be halogen, C ₁ -C ₁₀ alkyl, C ₂ -C _{10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl alkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, ^aryl, OR 8, NR ⁶ R ^8, SR ^6, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl Contact Optionally substituted with 1 to 3 groups independently selected from the group consisting of heterocyclylalkyl, provided that said ring contains two adjacent O atoms or two adjacent S atoms Without;

Alternatively, R ⁷ and R ⁸ are independently of each other, together with the atoms to which they are attached, one or more additional selected from the group consisting of O, S, SO, SO ₂ and NR ⁶ Of 3 to 10 membered cycloalkyl ring or heterocycloalkyl ring which may contain a heteroatom, each ring carbon may be halogen, C ₁ -C ₁₀ alkyl, C ₂ -C _{10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl alkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, ^aryl, OR 8, NR ⁶ R ^8, SR ^6, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl Contact Optionally substituted by 1 to 3 groups independently selected from the group consisting of and heterocyclylalkyl; provided that said ring contains two adjacent O atoms or two adjacent S atoms Without;

Alternatively, R ⁸ and R ⁹ are independently of each other, together with the atoms to which they are attached, one or more additional selected from the group consisting of O, S, SO, SO ₂ and NR ⁶ Of 3 to 10 membered cycloalkyl ring or heterocycloalkyl ring which may contain a heteroatom, each ring carbon may be halogen, C ₁ -C ₁₀ alkyl, C ₂ -C _{10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl alkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, ^aryl, OR 8, NR ⁶ R ^8, SR ^6, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl Contact Optionally substituted with 1 to 3 groups independently selected from the group consisting of heterocyclylalkyl, provided that said ring contains two adjacent O atoms or two adjacent S atoms Without;

Alternatively, R ⁶ and R ¹⁰ are independently of each other, together with the atoms to which they are attached, one or more additional selected from the group consisting of O, S, SO, SO ₂ and NR ⁶ Of 3 to 10 membered cycloalkyl ring or heterocycloalkyl ring which may contain a heteroatom, each ring carbon may be halogen, C ₁ -C ₁₀ alkyl, C ₂ -C _{10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl alkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, ^aryl, OR 8, NR ⁶ R ^8, SR ^6, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl And optionally substituted with 1 to 3 groups independently selected from the group consisting of heterocyclylalkyl, provided that the ring contains two adjacent O atoms or two adjacent S atoms Without;

Alternatively, R ⁸ and R ¹⁰ are independently of each other, together with the atoms to which they are attached, one or more additional selected from the group consisting of O, S, SO, SO ₂ and NR ⁶ Of 3 to 10 membered cycloalkyl ring or heterocycloalkyl ring which may contain a heteroatom, each ring carbon may be halogen, C ₁ -C ₁₀ alkyl, C ₂ -C _{10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10} cycloalkyl alkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, ^aryl, OR 8, NR ⁶ R ^8, SR ^6, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl And optionally substituted with 1-3 groups independently selected from heterocyclylalkyl, provided said ring does not contain two adjacent mutually O atoms or two adjacent mutually S atoms.

  In one embodiment, the pan-HER inhibitor is an inhibitor of one or more HER receptors selected independently from HER1, HER2, HER3, and HER4.

  In one embodiment, the biotherapeutic agent is administered parenterally.

  In one embodiment, the pan-HER inhibitor is a compound of formula (Ia),

(Ia)
The enantiomer or any one of these pharmaceutically acceptable salts.

  In one embodiment, the pan-HER inhibitor is valritinib,

Or a pharmaceutically acceptable salt thereof.

  In one embodiment, valritinib is used as the free base.

  Appropriate doses of valritinib are capable of directly inhibiting HER1, HER2 and HER4 and are believed to be capable of indirect inhibition for HER3.

  In one embodiment, the compound of formula (I) (including formula (Ia) and valritinib) at least inhibits the activity of HER1 and HER2, the activity of HER1 and HER4, or the activity of HER2 and HER4.

  In one embodiment, the compound of formula (I) (including formula (Ia) and valritinib) at least inhibits the activity of HER1, HER2 and HER4, eg directly inhibits the activity of HER1, HER2 and HER4.

  In one embodiment, the compound of formula (I) (including formula (Ia) and valritinib) inhibits the activity of HER1, HER2, HER3 and HER4, eg directly inhibits the activity of HER1, HER2, and HER4 And indirectly inhibit HER3 activity.

  In one embodiment, each dose of a compound of formula (I) (including formula (Ia) and valritinib) is in the range of 100-900 mg, for example, each dose is in the range of 300-500 mg (eg, 400 mg For example, once or twice a day (for example, twice a day).

  In some cases, reducing the initial dose to 300 mg or 200 mg once every two days may be effective for the patient.

  Administration of a compound of formula (I) (eg valritinib) in a non-continuous dosing regime (eg dosing every other day rather than daily, or no dosing for 1, 2 or 3 days after 4 days of daily dosing) It may be effective for other patients.

  In one embodiment, the compound of formula (I) (including formula (Ia) and valritinib) is administered orally.

  In one embodiment, the HER inhibitor is a combination of multiple HER inhibitors, such as a combination of valritinib and herceptin (trastuzumab) and / or pertuzumab.

  Surprisingly, the combination of valritinib and Herceptin shows a higher therapeutic activity than each alone.

  In one embodiment, the HER inhibitor is a combination of ado-trastuzuma-emtansine and valritinib.

  The DHODH inhibitor is 2- (3,5-difluoro-3′-methoxybiphenyl-4-ylamino) nicotinic acid (referred to herein as ASLAN003) or a pharmaceutically acceptable salt thereof, particularly: :

  In one embodiment, the DHODH inhibitor is administered daily, eg, once a day.

  Reference to a DHODH inhibitor or salt thereof as used herein includes providing the compound as a prodrug such as an ester that is converted in vivo to the active ingredient.

  In one embodiment, the DHODH inhibitor is administered orally.

  In one embodiment, the DHODH inhibitor and the pan-HER inhibitor (such as certain valritinib) are administered sequentially in a treatment plan, eg, administered on the same day.

  In one embodiment, a pan-HER inhibitor, such as valritinib, is administered twice daily, for example, at a dose within the ranges disclosed herein.

  In one embodiment, the DHODH inhibitor and HER inhibitor (such as a HER2 or panHER inhibitor) are co-administered at about the same time.

In one embodiment, the DHODH inhibitor is administered on a continuous period, eg, 1-60 months or longer, on a daily or weekly regimen, and the HER2 inhibitor or pan-HER inhibitor is intermittently interrupted during this period. For example, valritinib can be administered in one or more 28-day cycles. If the pan-HER inhibitor comprises an antibody molecule such as Herceptin, its administration protocol can be very different from the administration protocol for small molecule inhibitors. Herceptin can be administered, for example, in a regimen as follows (particularly in combination with cytotoxic chemotherapy):
1) Initial administration of 4 mg / Kg over 90 minutes;
2) Weekly administration of 2 mg / Kg over 30 minutes for the next 12 weeks; and 3) After 1 week of 2), start 6 mg / Kg over 30-90 minutes every 3 weeks.

  In one embodiment, the pan-HER inhibitor is administered on a continuous period, eg, 1-60 months or longer, on a daily or weekly regimen, and the DHODH inhibitor is administered intermittently during this period.

  Intermittent administration, as used herein, treatment is given and then treatment is stopped with the option of starting treatment again at some point in the future, or simply withdrawn for a certain period of time. Next, it refers to the period during which treatment is resumed according to the treatment plan.

  In one embodiment, the DHODH inhibitor is administered on a continuous period, for example 1-60 months or more, on a daily or weekly regimen, and the pan-HER inhibitor is on a continuous period, for example 1-60 months. As described above, it is administered on a daily or weekly regimen.

  In one embodiment, the DHODH inhibitor is administered on a daily or weekly regimen for an intermittent period of for example 1-60 months or more, and the pan-HER inhibitor is for an intermittent period of, for example, 1-60 months or more. Administered with a DHODH inhibitor on a daily or weekly regimen for an appropriate period of time.

  In one embodiment, the DHODH inhibitor and the pan-HER inhibitor are co-formulated.

  In one embodiment, the DHODH inhibitor is administered orally.

  In one embodiment, the HER inhibitor is administered orally, parenterally, or both, especially orally.

  In one embodiment, the HER inhibitor, such as a HER2 inhibitor, is administered orally or parenterally, eg intravenously.

  In one embodiment, the HER inhibitor, such as a pan-HER inhibitor, is administered orally.

  In one embodiment using a combination of HER inhibitors, one is administered orally and one is administered parenterally, eg intravenously.

  In one embodiment, the DHODH inhibitor and the pan-HER inhibitor are both administered orally.

  In one embodiment, the patient is a human.

  Advantages of using the DHODH inhibitor ASLAN003, even in monotherapy, include that cancer cells are killed by apoptosis as opposed to killing via necrotic mechanisms. This is surprising because DHODH inhibitors such as leflunomide and teriflunomide kill cancer cells through a necrotic mechanism.

  In one embodiment, the combination therapies of the present disclosure are advantageous and are advantageous in that, for example, they result in increased therapeutic activity compared to a monotherapy that includes one of the components.

  Increased activity can be any beneficial therapeutic effect of using the combination of the present disclosure, such as increased anti-tumor activity and / or reduced tendency for cancer to become resistant. Another advantage may be the therapeutic effect in patients who have failed one or more treatment lines. That is, in one embodiment, the patient population has a cancer that is resistant or refractory to a known treatment, such as cytotoxic chemotherapy.

  Unless the context indicates otherwise, refractory and resistance are used interchangeably herein to refer to cancer not responding to treatment or not fully responding to treatment.

  Combination therapy, as used herein, refers to the use of two or more treatment modalities over the same treatment period, ie the opposite of sequential therapy.

  Two or more treatment modalities, as used herein, refer to at least two treatment modalities that differ in their mode of action and / or activity and / or route of administration.

  In order to obtain the benefits of the combination therapy of the present disclosure, the HER inhibitor and DHODH inhibitor need to be administered within a time frame where the pharmacological effects of the HER inhibitor and DHODH inhibitor overlap, ie The treatment regimen of the treatment method partially matches in time. Those skilled in the art will understand what this means.

  Combination therapy, as used herein, refers to when an agent according to the present disclosure is administered with at least one additional therapeutic agent in one treatment regime. The treatment regimen may be administered in separate formulations at the same time or at different times, or may be a co-formulation of two or more therapeutic agents. The “first” agent used in the combination therapy according to the present disclosure may be administered prior to the additional therapeutic agent (s) of the present disclosure or administered concurrently with the additional therapeutic agent (s) of the present disclosure. Or it may be administered after the additional therapeutic agent (s) of the present disclosure.

  In one embodiment, additional therapeutic agent (s) such as anti-cancer treatments (especially chemotherapy) are used in combination with the disclosed monotherapy or combination therapy.

  In one embodiment, the therapeutic agent is a chemotherapeutic agent. A chemotherapeutic agent, as used herein, is intended to refer to a particular antineoplastic chemical or drug that is harmful to malignant cells and tissues, such as alkylating agents, antimetabolites , Anthracyclines, plant alkaloids, topoisomerase inhibitors, and other antitumor agents. Specific examples of chemotherapy include doxorubicin, 5-fluorouracil (5-FU), paclitaxel (eg, Abraxane or docetaxel), capecitabine, irinotecan, and platins such as cisplatin and oxaliplatin, or combinations thereof It is done. The appropriate dose may be chosen by the practitioner based on the nature of the cancer being treated and the patient.

  Co-administration, as used herein, refers to the administration of a DHODH inhibitor and a second therapeutic agent (such as a HER inhibitor and / or chemotherapy) at or near the same time (these active agents Are administered by the same or different routes).

  Inhibitors, as used herein, include, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45 when the associated biological activity is measured in an associated in vitro assay. , 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100%.

  Direct inhibition is when the inhibitor directly binds or physically blocks the binding interaction to inhibit biological activity or when the inhibitor inhibits activation by phosphorylation of the target molecule. .

  Indirect inhibition, as used herein, refers to a case where the biological activity in question is inhibited as a result of direct inhibition of a target other than that which is indirectly inhibited.

  Dihydroorotic acid dehydrogenase (DHODH) is the fourth step in the pyrimidine biosynthetic pathway, ie, the conversion of dihydroorotic acid to orotic acid with electron transfer to ubiquinone (cofactor Q) via a flavin mononucleotide intermediate. (Loffler MoI Cell Biochem, 1997). In contrast to parasites (Plasmodium falciparum) (McRobert et al MoI Biochem Parasitol 2002) and bacteria (E. coli) that exclusively use this new pathway as a source of pyrimidines, additional mammalian cells Has a salvage pathway.

  The cellular supply of pyrimidine bases in constitutive growth appears to be sufficient with a salvage pathway independent of DHODH. However, this new pathway is required for proliferation in cells with fast turnover, especially T lymphocytes and B lymphocytes. In these cells, DHODH inhibition stops cell cycle progression and ultimately cell growth by suppressing DNA synthesis (Breedveld F.C. Ann Rheum Dis 2000).

  There are several proposals that inhibition of mitochondrial cytochrome bc1, a component of electron transport complex III, leads to activation of tumor suppressor p53 and subsequent induction of apoptosis. The mitochondrial respiratory chain is linked to a novel pyrimidine biosynthetic pathway through the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH).

  It has been shown that dysfunction of novel pyrimidine biosynthesis by suppression of DHODH causes p53 activation.

  DHODH, as used herein, refers to a compound that inhibits the activity of dihydroorotic acid dehydrogenase, particularly in vivo. Aslan003 is disclosed in WO2008 / 077639 (incorporated herein by reference).

  Pan-HER inhibitors as used herein are ErbB family proteins, namely ErbB-1 (also known as HER1 and EGFR), ErbB-2 (HER2), ErbB-3 (HER3 ), And a molecule that inhibits at least two molecules from ErbB-4 (HER4). That is, a pan-HER inhibitor, as used herein, refers to a therapeutic agent (eg, chemical) that inhibits at least two HER receptors, eg, an inhibitor of HER1 and HER2.

  A biological therapeutic agent refers to a therapeutic agent based on a protein (including a polypeptide or peptide), such as an antibody or a binding fragment thereof, and a fusion protein complexed with a macromolecule, toxin or similar payload. And biomolecules.

  “Drug” as used herein refers to a chemical substance or organic chemical molecule having pharmacological activity.

  One example of a biological therapeutic agent complexed with a warhead suitable for use in the treatment of the present disclosure is trastuzumab emtansine.

  In one embodiment, the HER inhibitor is a HER dimerization inhibitor disclosed in WO 01/00244 and WO 01/100245 (incorporated herein by reference), such as pertuzumab. In one embodiment, the pan-HER inhibitor is a compound of formula (I) or (Ia) as disclosed above and in WO2005 / 016346 (incorporated herein by reference), in particular (R) -N4- [3-Chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (4-methyl-4,5, -dihydro-oxazol-2-yl) -quinazoline 3,4,6-diamine (Valritinib) or a pharmaceutically acceptable salt thereof.

  In one embodiment, valritinib is used as the free base.

  Examples of pharmaceutically acceptable salts include, but are not limited to, acid addition salts of strong mineral acids such as HCl and HBr salts, and strong organic acids such as methanesulfonate, tosylate and furoate. Addition salts thereof, for example, di- and tri-salts thereof such as ditosylate.

  In one embodiment, a combination therapy according to the present disclosure further comprises a RON inhibitor as disclosed, for example, in WO2008 / 058229 (incorporated herein by reference).

  In one embodiment, the combination therapy of the present disclosure comprises a checkpoint inhibitor, such as a CTLA4 inhibitor, PD-1 inhibitor or PD-L1 inhibitor, particularly an antibody or binding fragment thereof.

  In one embodiment, the monotherapy or combination therapy of the present disclosure further comprises a chemotherapeutic agent.

Chemotherapeutic Agents The disclosed methods of treatment (eg, combination therapy) may be used in combination with additional cancer treatment methods (eg, chemotherapy).

  Chemotherapeutic agents and chemotherapy or cytotoxic drugs are used interchangeably herein unless the context indicates otherwise.

  Chemotherapy, as used herein, is intended to refer to a particular antineoplastic chemical or drug that is “selectively” harmful to malignant cells and tissues, such as alkylating agents. Antimetabolites including thymidylate synthase inhibitors, anthracyclines, microtubule inhibitors including plant alkaloids, topoisomerase inhibitors, PARP inhibitors and other antitumor agents. Since many of these drugs naturally have serious side effects, the selective in this context is loosely used.

  The preferred dose may be selected by the practitioner based on the nature of the cancer being treated.

  Examples of alkylating agents that can be used in the methods of the present disclosure include alkylating agents such as nitrogen mustards, nitrosoureas, tetrazines, aziridines, platins and derivatives, and non-classical alkylating agents.

  Examples of platinum-containing chemotherapeutic agents (also called platins) include cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin and lipoplatin (lipoplatin of cisplatin), in particular cisplatin, Carboplatin and oxaliplatin are mentioned.

The dose of cisplatin ranges from about 20 to about 270 mg / m ² depending on the type of cancer. Often, the dosage is in the range of from about 70 to about 100 mg / ^{m 2.}

  Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan.

  Nitrosoureas include N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin. Tetrazines include dacarbazine, mitozolomide and temozolomide.

  Examples of aziridines include thiotepa, mitomycin and diaziquan (AZQ).

  Examples of antimetabolites that can be used in the methods of the present disclosure include antifolates (eg, methotrexate and pemetrexed), purine analogs (eg, thiopurines, such as azathioprine, mercaptopurine, thiopurine, fludarabine (phosphate) Salt forms), pentostatin and cladribine), pyrimidine analogs (eg, fluoropyrimidines such as 5-fluorouracil and its prodrugs such as capecitabine [Xeloda®]), floxuridine, gemcitabine, cytarabine, Examples include decitabine, raltitrexed (Tomdex) hydrochloride, cladribine and 6-azauracil.

  Examples of anthracyclines that can be used in the disclosed treatments include daunorubicin (daunomycin), daunorubicin (liposome), doxorubicin (adriamycin), doxorubicin (liposome), epirubicin, idarubicin, valrubicin (currently bladder And mitoxantrone, anthracycline analogues, especially doxorubicin.

  Examples of microtubule inhibitors that can be used in the disclosed methods of treatment include vinca alkaloids and / or taxanes.

  Vinca alkaloids include fully natural chemicals such as vincristine and vinblastine, as well as semi-synthetic vinca alkaloids such as vinorelbine, vindesine, and vinflunine.

  Examples of taxanes include paclitaxel, docetaxel, abraxane, cabazitaxel and derivatives thereof. Derivatives of taxanes used herein include, for example, re-formulations of taxanes such as taxol in micellar formulations, and derivatives may also be modified using taxonomic starting materials. Also included are chemical derivatives made.

  Topoisomerase inhibitors that can be used in the methods of the present disclosure include type I topoisomerase inhibitors, type II topoisomerase inhibitors, and type II topoisomerase poisons. Type I inhibitors include topotecan, irinotecan, indotecan and indimitecan. Type II inhibitors include genistein and ICRF193 having the structure:

  Type II poisons include amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin, and fluoroquinolone antibiotics.

  In one embodiment, the chemotherapeutic agent is a PARP inhibitor.

  In one embodiment, the combination of chemotherapeutic agents used is, for example, platin, and 5-FU or a prodrug thereof, such as cisplatin or oxaplatin, and capecitabine or gemcitabine, such as FOLFOX.

  In one embodiment, chemotherapy includes a combination of chemotherapeutic agents, particularly cytotoxic chemotherapeutic agents.

  In one embodiment, the combination chemotherapy includes platin, such as cisplatin, and fluorouracil or capecitabine.

  In one embodiment, the combination chemotherapy is capecitabine and oxaliplatin (Xelox).

  In one embodiment, the chemotherapy is a combination of folinic acid and 5-FU, optionally combined with oxaliplatin.

In one embodiment, the chemotherapy is a combination of folinic acid, 5-FU and irinotecan (FOLFIRI), optionally combined with oxaliplatin (FOLFIRINOX). The dosing regimen, for example, consists of: irinotecan (180 mg / m ² , IV over 90 minutes) and simultaneously folinic acid (400 mg / m ² [or 2 × 250 mg / m ² ], IV over 120 minutes); fluorouracil (400~500mg / m ^2, IV bolus), then fluorouracil (2400~3000mg / m ^2, 46 hours over intravenous infusion). This cycle is usually repeated every 2 weeks. The above dosage may vary from cycle to cycle.

  In one embodiment, the combination chemotherapy is a microtubule inhibitor such as vincristine sulfate, epothilone A, N- [2-[(4-hydroxyphenyl) amino] -3-pyridinyl] -4 methoxybenzenesulfonamide ( ABT-751), taxol-derived chemotherapeutic agents such as paclitaxel, abraxane, or docetaxel or combinations thereof are used.

  In one embodiment, the chemotherapy combination uses an mTor inhibitor. Examples of mTor inhibitors include everolimus (RAD001), WYE-354, KU-0063794, papamycin (sirolimus), temsirolimus, deforolimus (MK-8669), AZD8055 and BEZ235 (NVP-BEZ235). .

  In one embodiment, the chemotherapy combination uses a MEK inhibitor. Examples of MEK inhibitors include AS703026, CI-1040 (PD184352), AZD6244 (Selmethinib), PD318088, PD0325901, AZD8330, PD98059, U0126-EtOH, BIX02189 or BIX02188.

  In one embodiment, the chemotherapy combination uses an AKT inhibitor. Examples of AKT inhibitors include MK-2206 and AT7867.

  In one embodiment, an aurora kinase inhibitor is used for the combination. Examples of Aurora kinase inhibitors include Aurora A inhibitor I, VX-680, AZD1152-HQPA (Barasertib), SNS314 mesylate, PHA-680632, ZM-447439, CCT129202 and Hesperadin. It is done.

  In one embodiment, the chemotherapy combination is N- [4-({4- [3- (3-tert-butyl-1-p-tolyl-1H-pyrazole-, eg, disclosed in WO2010 / 038086]. A p38 inhibitor such as 5 yl) ureido] naphthalen-1-yloxy} methyl) pyridin-2-yl] -2-methoxyacetamide is used.

  In one embodiment, a Bcl-2 inhibitor is used in combination. Examples of Bcl-2 inhibitors include obatoclax mesylate, ABT-737, ABT-263 (Navitocrax) and TW-37.

  In one embodiment, the chemotherapy combination comprises an antimetabolite such as capecitabine (Xeloda), fludarabine phosphate, fludarabine (fludara), decitabine, raltitrexed (Tomdex), gemcitabine hydrochloride and cladribine.

  In one embodiment, the chemotherapy combination comprises ganciclovir that can help control immune responses and / or tumor vasculation.

  In one embodiment, the chemotherapy includes a PARP inhibitor.

  In one embodiment, the one or more therapies used in the methods herein are continuous or frequent treatments with low doses of anticancer agents, often with other therapies Metronomic therapy given at the same time.

  In one embodiment, the use of multiple cycles of treatment (eg, chemotherapy) is provided, for example 2, 3, 4, 5, 6, 7, 8 times.

  In one embodiment, the treatment of the present disclosure is used after chemotherapy.

  In one embodiment, the treatment of the present disclosure is used prior to chemotherapy.

  In one embodiment, the dose of chemotherapy used in the treatment of the present disclosure is lower than the dose of chemotherapy used in “monotherapy” (although monotherapy uses a combination of chemotherapeutic agents) May include the dose of chemotherapy used in some cases).

  In one embodiment, the agent is combined with a cancer treatment, eg, treatment of cachexia (eg, cancer cachexia), supplemental treatment, eg, S-pindolol, S-mepindolol or S-bopindolol. Administered. When single doses or multiple doses given as multiple doses are administered within a day, a suitable dose may be in the range of 2.5 mg to 100 mg, for example 2.5 mg to 50 mg per day.

Treatment As used herein, treatment refers to a patient having a disease or disorder (eg, cancer) and administration of an agent according to the present disclosure to stabilize the disease, delay the disease. Refers to being ameliorated, disease ameliorated, disease remission maintained, or disease cured. Treatment as used herein includes administration of an agent according to the present disclosure for treatment or prevention. The present disclosure is described in the context of a method for treating a patient. However, the present disclosure extends to the use of the therapeutic methods described herein for use in therapy, particularly for the treatment of cancers such as those described herein. Also provided is the use of a compound described herein for the manufacture of a medicament for the treatment of cancer, in particular the cancer described herein.

  In one embodiment, the combination therapy according to the present disclosure is used as a postoperative adjuvant therapy for cancer, for example after surgery to remove some or all of the cancerous cells.

  In one embodiment, the treatment methods described in this disclosure are used as neoadjuvant therapy, for example, prior to surgery to remove some or all of the cancerous cells.

  In one embodiment, the therapeutically effective amount (eg daily dose) of the DHODH inhibitor is administered within a range of 10 mg to 1000 mg, such as 50 to 500 mg, eg 50, 100, especially once daily. 150, 200, 250, 300, 350, 400, 450, 500 mg.

  In one embodiment, a pan-HER inhibitor, such as a compound of formula (I) or (Ia) (especially valritinib), for example at a dose in the range of 100 mg to 900 mg per dose, in particular 300 mg or 400 mg or 500 mg. Are administered every other day.

  The active ingredient used in the therapeutic methods of the present disclosure is typically provided in the form of a pharmaceutical formulation comprising one or more excipients, diluents or carriers.

  In one embodiment, the compound of formula (I), (Ia) or valritinib is administered as a pharmaceutical formulation comprising one or more pharmaceutically acceptable excipients.

  In the context of this specification, “comprising” shall be interpreted as “including”.

  Embodiments of the invention that include certain features / elements are intended to cover other embodiments that “consist” or “consist essentially” of related elements / features.

  If technically appropriate, the embodiments of the present invention may be combined.

  Technical references such as patents and applications are hereby incorporated by reference.

Antoine et.al, 2012. Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. Journal of Hepatology, 56 (5), 1070-1079. Stutchfield et.al, 2015.CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure.Gastroenterology, 149 (7), 1896-1909.

  Any embodiment specifically and explicitly described herein, alone or in combination with one or more other embodiments, does not constitute a basis for waiver.

  The headings herein are used to divide this document into sections, and are not intended to be used to interpret the meaning of the disclosure provided herein.

The ALT1 level of Cohort 5 is shown. The miR122 level of cohort 5 is shown. Total K18 (necrosis and apoptosis ULN-380 U / l) is shown. Caspase truncated K18 (apoptotic ULN-280U / l) is shown. The ALT1 level of cohort 6 is shown. The miR122 level of cohort 6 is shown. The ALT1 level of cohort 7 is shown. Cohort 7 miR122 levels are shown. Cohort 7 total K18 (necrosis and apoptosis ULN-380U / l) is shown. The caspase cleaved form K18 of cohort 7 (apoptotic ULN-280U / l) is shown. The ALT1 level of the older cohort 8 is shown. The miR122 level of the older cohort 8 is shown. Total K18 (necrosis & apoptotic ULN-380 U / l) of the older cohort 8 is shown. An older cohort 8 caspase truncated K18 (apoptotic ULN-280U / l) is shown. The ALT1 level of cohort 9 is shown. The miR122 level of cohort 9 is shown. Total K18 (necrosis & apoptotic ULN-380 U / l) of the older cohort 9 is shown. Caspase truncated K18 (apoptotic ULN-280U / l) of the older cohort 9 is shown. The CSF-1 level of cohort 5 is shown. The CSF-1 level of cohort 7 is shown. The CSF-1 level of cohort 8 is shown. The CSF-1 level of cohort 9 is shown. The cytotoxic effects and mechanistic biomarker analysis of various concentrations of ASLAN003 and teriflunomide are shown. The concentration that results in 50% activity is listed next to the compound. Same as above. The cytotoxic effects and mechanistic biomarker analysis of ASLAN003 and teriflunomide at various time points are shown. Same as above. As can be seen from apoptosis markers such as cytokeratin 18 (K18) cleavage, caspase 3 activation and DNA laddering, ASLAN003 is shown to cause apoptosis. As can be seen from markers such as cytokeratin 18 cleavage, caspase 3 activation and DNA laddering, ASLAN003 is shown to cause apoptosis. Cytotoxic effects and mechanistic biomarker analysis of ASLAN003 (A) and teriflunomide (T) in the presence and absence of DHODH substrate (dihydroorotic acid, DHO) and product (orotic acid / uridine, O / U) Is shown. No compound was added to the negative control (Con). Cytotoxic effects and mechanistic biomarker analysis of ASLAN003 (A) and teriflunomide (T) in the presence and absence of DHODH substrate (dihydroorotic acid, DHO) and product (orotic acid / uridine, O / U) Is shown. No compound was added to the negative control (Con). The mitochondrial function of ASLAN003 and teriflunomide is shown. The effects on the electron transport system by ASLAN003 (black bar) and teriflunomide (white bar) are shown. The effects on the electron transport system by ASLAN003 (black bar) and teriflunomide (white bar) are shown. Shown is ASLAN003 induction of CD11b and CD14 in various AML cell lines. Same as above. The NBT reduction activity of ASLAN003 is shown. Shown is Giemsa staining of MOLM-14 cells after treatment with ASLAN003 or control for 96 hours. Shown are the results of NBT assay of MOLM-14 cells after treatment with ASLAN003 or control for 96 hours. Shown is Giemsa staining of THP-1 cells after 96 hours treatment with ASLAN003 or control. Shown are the results of NBT assay of THP-1 cells after treatment with ASLAN003 or control for 96 hours. Shown is Giemsa staining of NB-4 cells after treatment with ASLAN003 or control for 96 hours. Shown are the results of the NBT assay of NB-4 cells after treatment with ASLAN003 or control for 96 hours.

Example 1
Objectives and study design In a phase 1 safety and tolerability study of ASLAN003 in healthy volunteers, ASLAN003 was found to be well tolerated. However, a slight increase in liver enzymes (ALT / AST) was observed in some healthy individuals (older than 55 years old and weighing less than 55 kg). To understand the liver-specific effects of ASLAN003, liver biomarker tests were performed using patient samples from the Phase 1 study.

  In addition, the effects of ASLAN003 and teriflunomide on cytotoxicity, modulation of miR-122 and p53 activation, and mitochondrial function of primary human hepatocytes and paired cancer cells / cancer cell lines will also be tested.

Methods: Test article / compound, animal model, findings and protocol deviations during the study, tumor efficacy and tolerability data analysis, biomarker analysis

Patient samples for biomarker analysis Patient plasma samples from the following cohorts were tested:
Cohort 5: 100 mg / kg once a day for healthy young male volunteers Cohort 6: 200 mg / kg once a day for healthy young male volunteers Cohort 7: 400 mg / kg once per day for healthy young male volunteers Cohort 8: 200 mg / kg once a day for healthy elderly volunteers Cohort 9: 100 mg / kg once a day for healthy elderly volunteers Biomarker analysis

  The biomarker test set will include miR-122, alanine aminotransferase (ALT), total keratin-18 (K18) and caspase truncated K18, total and acetyl-HMGB1 and CSF1. An effective protocol for the clinical utility of this biomarker test set in human drug-induced liver injury has been published. MicroRNA-122 (miR-122) is an early and sensitive marker of liver damage. ALT isoforms 1 and 2 are used to measure gut-specific ALT and total ALT to determine whether ASLAN003-induced ALT is derived from the gut or liver.

  Induction of apoptosis and necrosis by ASLAN003 and teriflunomide was determined by measuring total K18 and caspase-cleaved K18 (Antoine et. Al, 2012). Liver regeneration is monitored by increased CSF-1 expression (Stutchfield et. Al, 2015).

In Vitro Testing Fresh primary human hepatocytes were obtained from tissues excised after informed consent during hepatectomy (N = 6). These hepatocytes are incubated with ASLAN003 or teriflunomide, followed by ATP analysis (cytotoxicity), kinetic analysis of mitochondrial health (Seahorse), p53 activation analysis (luciferase expression reporter-alternative toxicant) Kinetic markers), as well as K18 and caspase-3 analysis (clinical data-alternative toxicokinetic markers based on cell death mode).

Biomarker analysis Increased levels of ALT1 and miR-122 confirmed that the increased ALT / AST observed in the ASLAN003 clinical trial was due to the liver (FIGS. 1, 3, 4, 6 and 6). 8).

  Increases in total K18 and caspase-cleaved K18 were observed and these increases were dose and time dependent (FIGS. 2, 5, 7, and 9). In Cohort 5 (100 mg / kg once a day for healthy young male volunteers) no increase in total K18 and caspase-cleaved K18 was observed. The increase in total K18 and caspase-cleaved K18 is higher in the older cohorts (cohorts 8 and 9) compared with the younger cohorts (cohorts 8 and 9), consistent with increases in ALT1 and miR-122 in the same patient ing. Circulating CSF-1 levels were also found to be upregulated in these same subjects towards the end of the protocol, indicating liver regeneration. Up-regulation of CSF-1 levels was comparable to the value observed during liver regeneration after hepatectomy.

  The apoptotic index (0.65-0.86) confirms that hepatocyte apoptosis is the main cell death mode induced by ASLAN003 in men (similarly-conserved mechanism across all cohorts). Consistent with acute liver injury (0.75-1.0) induced by therapeutic doses of paracetamol than severe overdose (survival = 0.1-0.5, death / LT ≦ 0.1).

In vitro studies Dose-dependent cytotoxicity against primary human hepatocytes was observed in both ASLAN003 and teriflunomide (Figure 12). However, given the results for total K18 and caspase-cleaved K18, cytotoxicity was found to be induced by these compounds by different mechanisms: ASLAN003 induced apoptosis and teriflunomide induced necrosis (FIG. 12). Consistent with this finding, ASLAN003 was found to be more potent than teriflunomide in p53 activation. ASLAN003 left similar results for K18 in clinical and in vitro studies. ASLAN003 induced apoptosis during 24 hours, while teriflunomide induced necrosis after 24 hours (FIG. 13).

  The apoptotic effect of ASLAN003 was confirmed using the results of immunocytochemistry of K18, Western blot of caspase-3 activation and DNA laddering (FIG. 14). The apoptotic effect of ASLAN003 was rescued by the addition of DHODH products orotic acid and uridine, but not by the addition of DHODH substrate. This indicates that the apoptotic effect was specific for DHODH inhibition (FIG. 15).

  Both ASLAN003 and teriflunomide induced mitochondrial dysfunction in primary human hepatocytes, leading to increased proton leakage and decreased ATP-related respiration. Most importantly, ASLAN003 and teriflunomide did not alter pre-respiratory capacity, indicating that both compounds inhibited basal mitochondrial function but did not affect maximal mitochondrial function. This is shown (FIG. 16). As expected, both ASLAN003 and teriflunomide inhibited only electron transport complex III (FIG. 17).

Conclusion High doses of ASLAN003 caused reversible hepatocyte apoptosis through induction of p53.

Example 2
In vitro analysis of ASLAN003 against AML cell lines at various blast differentiation stages from various FAB classification subtypes

  AML cell lines were dosed with various concentrations of ASLAN003, and cell line differentiation was observed by flow cytometry through elevated expression of CD11b and CD14 on the cell surface. In addition, differentiation was determined from morphological observation after Wright-Giemsa staining using NBT assay.

  The results are shown in FIGS. 18-25 and summarized in the table above.

  The myeloid differentiation effect of ASLAN003 was observed in KG-1, MOLM-14 and THP-1 cell lines. However, administration of ASLAN003 to HL-60 and NB-4 AML cell lines did not induce the observed differentiation effects.

Claims (41)

  2- (3,5-Difluoro-3'methoxybiphenyl-4-ylamino) nicotinic acid or a pharmaceutically acceptable salt thereof, which is a DHODH inhibitor, for use in the manufacture of a medicament for treating blood cancer.   The hematological cancer is selected from myeloma, lymphoma, leukemia, chronic myeloproliferative disorder, undefined monoclonal hypergammaglobulinemia, myelodysplastic syndrome, plasma exchange amyloidosis and plasmacytoma The DHODH inhibitor according to claim 1.   The DHODH inhibitor for use according to claim 2, wherein the hematological cancer is myeloma.   The DHODH inhibitor for use according to claim 2 or 4, wherein the hematological cancer is lymphoma.   The DHODH inhibitor for use according to claim 4, wherein the lymphoma is selected from Hodgkin lymphoma and non-Hodgkin lymphoma.   Lymphoma is anaplastic large cell lymphoma, hemangioimmunoblastic lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, blastic NK cell lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, diffuse large cell Type B cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mantle cell lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, 6. A DHODH inhibitor for use according to any one of claims 2 to 5, selected independently from Waldenstrom macroglobulinemia and combinations thereof.   The DHODH inhibitor for use according to any one of claims 2 to 6, wherein the hematological cancer is a chronic myeloproliferative disease.   8. DHODH inhibition for use according to any one of claims 2 to 7, wherein the chronic myeloproliferative disorder is selected from essential thrombocythemia, chronic idiopathic myelofibrosis, and true primary erythrocytosis. Agent.   The DHODH inhibitor for use according to any one of claims 2 to 8, wherein the blood cancer is leukemia.   The leukemia is independently selected from AML (acute myeloid leukemia), ALL (acute lymphoblastic leukemia), CML (chronic myeloid leukemia) and CLL (chronic lymphocytic leukemia) and combinations thereof. A DHODH inhibitor for the use described in 1.   10. A DHODH inhibitor for use according to claim 8 or 9, wherein the leukemia is selected from hairy cell leukemia, acute lymphoblastic leukemia, and chronic lymphoblastic leukemia.   Leukemia is acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, hairy cell leukemia, T cell prolymphocytic leukemia, large granular lymphocytic leukemia, adult T cell Claims independently selected from leukemia, clonal eosinophilia, T-cell granular leukemia, NK cell leukemia, adult T cell leukemia and combinations thereof A DHODH inhibitor for the use according to any one of 9-11.   13. A DHODH inhibitor for use according to claim 12, wherein the leukemia is AML.   13. A DHODH inhibitor for use according to claim 12, wherein the leukemia is ALL.   13. A DHODH inhibitor for use according to claim 12, wherein the leukemia is CML.   13. A DHODH inhibitor for use according to claim 12, wherein the leukemia is CLL.   17. A DHODH inhibitor for therapeutic use according to any one of claims 1 to 16, wherein a DHODH inhibitor is used in combination therapy with a second therapy.   17. A DHODH inhibitor for use according to claim 16, wherein the second treatment is an inhibitor of DNA repair.   19. A DHODH inhibitor for use according to claim 17 or 18, wherein the inhibitor is a small molecule therapy.   20. A DHODH inhibitor for use according to claim 18 or 19, wherein the inhibitor mechanism is via a base excision repair pathway.   21. A DHODH inhibitor for use according to claim 20, wherein the inhibitor target is independently selected from APE1, Polβ, FEN1, and PARP.   The inhibitor is also TRC102, (2E) -2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl) methylene] -undecanoic acid [E3330 NCS-667715 and NSC-124854, 8-oxoguanine, Tanespimycin, Luminespib, Alvespimycin, Ganetespib, Letaspimycin, 6-amino-8-[(6-iodo-1,3 -Benzodioxol-5-yl) thio] -N- (1-methylethyl) -9H-purine-9-propanamine (PU-H71), 4- [2-carbamoyl-5- [6,6- Dimethyl-4-oxo-3- (trifluoromethyl) -5,7-dihydroindazol-1-yl] anilino] cyclohexyl] 2-aminoacete (SNX-5422), Luminespib (resorcyinylic), 2- (2-ethyl-3,5-dihydroxy-6- (3-methoxy-4- (2-morpholinoethoxy) benzoyl) phenyl) -N , N-bis (2-methoxyethyl) acetamide (KW-2478), AT13387, 5,6-bis ((E) -benzylideneamino) -2-thioxo-2,3-dihydropyrimidin-4 (1H) -one 22. A DHODH inhibitor for use according to claim 20 or 21 selected from (SCR7) as well as combinations of two or more thereof.   23. A DHODH inhibitor for use according to any one of claims 20 to 22, wherein the inhibitor is a PARP inhibitor such as a PARP-1 inhibitor and / or a PARP-2 inhibitor.   24. The PARP inhibitor according to claim 23, wherein the PARP inhibitor is independently selected from olaparib, lucaparib, nilaparib, iniparib, tarazoparib, beliparib, CEP9722, E7016, BGB-290, AZD-2461, 3-aminobenzamide and combinations thereof. DHODH inhibitor for use.   25. A DHODH inhibitor for use according to any one of claims 18 to 24, wherein the mechanism of the inhibitor is via a mismatch repair pathway.   26. A DHODH inhibitor for use according to any one of claims 18 to 25, wherein the inhibitor mechanism is via a nucleotide excision pathway.   27. DHODH inhibition for use according to claim 26, wherein the inhibitor is independently selected from 7-hydroxystaurosporine [UCN-01], trabectedin, MCI13E, NERI01 and combinations of two or more thereof. Agent.   28. A DHODH inhibitor for use according to any one of claims 18 to 27, wherein the inhibitor mechanism is via a double-strand break repair pathway.   29. A DHODH inhibitor for use according to claim 28, wherein the mechanism of the inhibitor is via a non-homologous end joining pathway.   30. A DHODH inhibitor for use according to claim 28 or 29, wherein the inhibitor is via a homologous recombination pathway.   31. A DHODH inhibitor for use according to any one of claims 17 to 30, wherein the treatment is a topoisomerase inhibitor, such as a topoisomerase I and / or II inhibitor.   32. A DHODH inhibitor for use according to claim 31, wherein the topoisomerase inhibitor is independently selected from irinotecan, topotecan, camptothecin, lamellarin D and combinations thereof.   Topoisomerase inhibitors are etoposide (VP-16), teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, 3-hydroxy-2-[(1R) -6-isopropenyl-3-methyl- 33. DHODH for use according to claim 31 or 32, independently selected from cyclohex-2-en-1-yl] -5-pentyl-1,4-benzoquinone (HU-331) and combinations thereof Inhibitor.   Hematological cancer treatment is a pan-HER inhibitor such as (R) -N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (4-methyl-4,5, -dihydro- 34. A DHODH inhibitor for use according to any one of claims 1 to 33, further comprising oxazol-2-yl) -quinazoline-4,6-diamine or a pharmaceutically acceptable salt thereof.   35. A DHODH inhibitor for use according to claim 34, wherein the pan-HER2 inhibitor is administered parenterally.   35. A DHODH inhibitor for use according to claim 34, wherein the pan-HER2 inhibitor is administered orally.   37. A DHODH inhibitor for use according to claim 36, wherein the pan-HER2 inhibitor is administered every other day.   38. A DHODH inhibitor for use according to claim 36 or 37, wherein each dose of pan-HER inhibitor is in the range of 100-900 mg.   39. A DHODH inhibitor for use according to claim 38, wherein each dose is in the range of 300-500 mg.   40. A DHODH inhibitor for use according to any one of claims 1 to 39, wherein the DHODH inhibitor provides an anti-cancer effect via induction of p53.   41. A DHODH inhibitor for use according to any one of claims 1 to 40, wherein the DHODH inhibitor is administered orally, e.g. once a day.