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WO2019118855A1 - Composés et compositions pour la prévention et/ou le traitement du cancer - Google Patents

Composés et compositions pour la prévention et/ou le traitement du cancer Download PDF

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Publication number
WO2019118855A1
WO2019118855A1 PCT/US2018/065708 US2018065708W WO2019118855A1 WO 2019118855 A1 WO2019118855 A1 WO 2019118855A1 US 2018065708 W US2018065708 W US 2018065708W WO 2019118855 A1 WO2019118855 A1 WO 2019118855A1
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group
inhibitor
compound
alkyl
estrogen
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Todd RIDKY
Christopher Natale
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University of Pennsylvania Penn
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University of Pennsylvania Penn
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • Cancer is the term used to describe a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Over 100 types of cancers affect humans. All tumor cells show six hallmarks, which are required to produce a malignant tumor: cell growth and division absent proper signals; continuous growth and division even given contrary signals; avoidance of programmed cell death; limitless number of cell divisions; blood vessel generation; and tissue invasion and metastases formation.
  • Cancer is characterized by failed tissue growth regulation.
  • genes that regulate cell growth and differentiation must be altered.
  • Such genes are divided into two broad categories: oncogenes (which promote cell growth and reproduction), and tumor suppressor genes (which inhibit cell division and survival).
  • oncogenes which promote cell growth and reproduction
  • tumor suppressor genes which inhibit cell division and survival.
  • Malignant transformation can occur through formation of novel oncogenes, inappropriate over-expression of normal oncogenes, or under-expression or disabling of tumor suppressor genes.
  • malignant transformations require changes in multiple genes: through large-scale mutations (including transposition, deletion, or gain of a chromosome or part thereof), or small-scale mutation (including point mutations, deletions, and insertions of a specific gene; or integration of genomic material from a DNA virus or retrovirus).
  • the invention provides a method of treating or preventing pancreatic cancer in a subject.
  • the invention further provides a method of treating or preventing Merkel cell carcinoma (MCC) in a subject.
  • MCC Merkel cell carcinoma
  • the invention further provides a composition comprising (i) estrogen and/or GPER agonist and (ii) an immune checkpoint inhibitor.
  • the invention further provides a kit comprising (i) estrogen and/or GPER agonist and (ii) an immune checkpoint inhibitor, and instructional material for use thereof in treating or preventing a cancer in a subject.
  • the method comprises administering to the subject in need thereof a therapeutically effective amount of estrogen and/or a selective G protein-coupled estrogen receptor (GPER) agonist. In certain embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of estrogen and/or a GPER agonist.
  • GPER G protein-coupled estrogen receptor
  • the subject is further administered at least one additional anticancer agent. In certain embodiments, the subject is further administered at least one immunotherapeutic agent.
  • the pancreatic cancer is K-Ras driven.
  • the pancreatic cancer comprises at least one selected from the group consisting of pancreatic adenocarcinoma, acinar cell carcinoma, cystadenocarcinoma, pancreatoblastoma, adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, solid pseudopapillary tumor, and pancreatic mucinous cystic neoplasm.
  • the at least one immunotherapeutic agent comprises an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is selected from the group consisting of a PD-l inhibitor, PD-L1 inhibitor, CTLA-4 inhibitor, TIGIT inhibitor, LAG3 inhibitor, IDO(l/2) inhibitor, and B7-H3 inhibitor.
  • the PD-L1 inhibitor comprises avelumab.
  • the estrogen and/or GPER agonist, and the at least one additional anticancer agent are co-administered to the subject. In certain embodiments, the estrogen and/or GPER agonist, and the at least one additional anticancer agent, are co- formulated.
  • the estrogen and/or GPER agonist, and the at least one immune checkpoint inhibitor are co-administered to the subject. In certain embodiments, the estrogen and/or GPER agonist, and the at least one immune checkpoint inhibitor, are co- formulated.
  • administering the estrogen and/or GPER agonist, and the at least one additional anticancer agent, to the subject allows for greater treatment efficacy than administering the estrogen and/or GPER agonist, and the at least one additional anticancer agent, separately.
  • administering the estrogen and/or GPER agonist, and the at least one additional anticancer agent, to the subject enhances the anti-cancer activity of the estrogen and/or GPER agonist, and the at least one additional anticancer agent, in the subject.
  • administering the estrogen and/or GPER agonist, and the at least one immune checkpoint inhibitor, to the subject allows for greater treatment efficacy than administering the estrogen and/or GPER agonist, and the at least one immune checkpoint inhibitor, separately.
  • administering the estrogen and/or GPER agonist, and the at least one immune checkpoint inhibitor, to the subject enhances the anti-cancer activity of the estrogen and/or GPER agonist, and the at least one immune checkpoint inhibitor, in the subject.
  • the estrogen and/or GPER agonist is/are the only anticancer agent administered to the subject.
  • the estrogen and/or GPER agonist are/is the only anticancer agent administered to the subject in an amount sufficient to treat or prevent the pancreatic cancer in the subject.
  • the estrogen and/or GPER agonist are/is the only anticancer agent administered to the subject in an amount sufficient to treat or prevent the MCC in the subject.
  • the estrogen comprises at least one selected from the group consisting of estrone (El), estradiol (E2), estriol (E3), estetrol (E4), l7P-estradiol, 27- hydroxycholesterol, dehydroepiandrosterone (DHEA), 7-oxo-DHEA, 7a-hydroxy-DHEA, l6a-hydroxy-DHEA, 7P-hydroxyepiandrosterone, A 4 -androstenedione, A 5 -androstenediol, 3a-androstanediol, 3P-androstanediol, 2-hydroxy estrone, l6-hydroxyestrone, estradiol cypionate, estradiol valerate, estradiol acetate, estradiol benzoate, ethinyl estradiol (EE), mestranol, moxestrol, quinestrol, diethylstilbestrol benzestrol,
  • the GPER agonist comprises at least one selected from the group consisting of G-l, tamoxifen, fulvestrant, and raloxifene, or a salt, solvate, tautomer, enantiomer or diastereoisomer thereof.
  • the GPER agonist comprises at least one selected from the group consisting of:
  • R 2 is selected from the group consisting of C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;
  • bond a is a single or double bond, such that:
  • R 3 and R 4 are H
  • R 3 is selected from the group consisting of H, -OH, -OAc, and halo
  • R 4 is selected from the group consisting of H, -OH, -OAc, and -S(o- nitrophenyl); or R 3 and R 4 combine to form a diradical selected from the group consisting of -CH 2 -, -0CH 2 0-, -0CH(CH 3 )0-, and -0C(CH 3 ) 2 0-;
  • R 5 is selected from the group consisting of H, benzyl, C 1 -C 4 alkyl, and acetyl;
  • s is selected from the group consisting of H, halo, -N0 2 , C 1 -C 4 alkyl, -CoCH, -CoC- Si(CH 3 ) 3 (or -CoC-TMS), -O-benzyl, -OH, -OAc, C 1 -C 4 alkoxy, -COOH, and -COO(Ci-C 4 alkyl);
  • R 7 is selected from the group consisting of H, halo, -N0 2 C 1 -C 4 alkyl, -OH, -OAc, and C 1 -C 4 alkoxy;
  • R 9 is selected from the group consisting of H, halo, -N0 2 , C 1 -C 4 alkyl, -OH, -OAc, and C 1 -C 4 alkoxy,
  • Rio is selected from the group consisting of H, C 1 -C 4 alkyl, and halo;
  • each occurrence of benzyl is independently optionally substituted with at least one group selected from the group consisting of C 1 -C 4 alkyl, -OH, C 1 -C 4 alkoxy, halo, and -N0 2 ; and
  • R 2 is C 1 -C 4 alkyl
  • R 5 is selected from the group consisting of H, benzyl and C 1 -C 4 alkyl;
  • R 8 and R 9 are independently selected from the group consisting of H and C 1 -C 4 alkoxy, or R 8 and R 9 combine to form a diradical selected from the group consisting of -0CH 2 0-, - 0CH(CH 3 )0- and -0C(CH 3 ) 2 0-,
  • the GPER agonist comprises at least one selected from the group consisting of:
  • R 2 is C 1 -C 4 alkyl
  • bond a is a single or double bond, such that: if bond a is a double bond, R 3 and R 4 are H, and
  • R 3 and R4 are independently selected from the group consisting of H and -OH, or R 3 and R4 combine to form a diradical selected from the group consisting of -0CH 2 0-, -0CH(CH 3 )0- and -0C(CH 3 ) 2 0-;
  • R 5 is selected from the group consisting of H, benzyl and C 1 -C 4 alkyl;
  • s is selected from the group consisting of H and halo
  • R 8 and R9 are independently selected from the group consisting of H and C1-C4 alkoxy, or R 8 and R9 combine to form a diradical selected from the group consisting of -0CH 2 0-, - 0CH(CH 3 )0- and -0C(CH 3 ) 2 0-;
  • R 2 is C 1 -C 4 alkyl
  • R 5 is selected from the group consisting of H, benzyl and C 1 -C 4 alkyl;
  • R 7 and R 8 are independently selected from the group consisting of H and C1-C4 alkoxy, or R 7 and R 8 combine to form a diradical selected from the group consisting of -OCH 2 0-, - OCH(CH 3 )0- and -0C(CH 3 ) 2 0-,
  • the GPER agonist comprises at least one selected from the group consisting of: G-l; CMPD1 (rel-l-((3aS,4R,9bR)-4-(benzo[d][l,3]dioxol-5-yl)- 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl)ethan-l-one); CMPD2 (rel-l- ((3aS,4R,9bR)-4-(6-bromobenzo[d][l,3]dioxol-5-yl)-5-methyl-3a,4,5,9b-tetrahydro-3H- cyclopenta[c]quinolin-8-yl)ethan-l-one); CMPD3 (rel-l-((3aS,4R,9bR)-4-(6- bromobenzo[d][l,3]dioxol-5-
  • the subject is further administered at least one additional anticancer treatment.
  • the at least one additional anticancer treatment comprises chemotherapy, an engineered chimeric antigen receptor (CAR) T-cell, and/or radiation therapy.
  • the chemotherapy is selected from the group consisting of a histone deacetylase inhibitor (HD AC), temozolomide, dacarbazine (DTIC), vemurafenib, dabrafenib and trametinib.
  • HD AC histone deacetylase inhibitor
  • DTIC dacarbazine
  • vemurafenib dabrafenib
  • trametinib trametinib.
  • the estrogen and/or GPER agonist is/are independently administered to the subject by at least one administration route selected from the group consisting of inhalational, oral, rectal, vaginal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, intracranial, and intravenous.
  • the subject is a mammal. In certain embodiments, the mammal is human.
  • FIGs. 1 A-1K illustrate results that indicate that GPER signaling is tumor suppressive in pancreatic ductal adenocarcinoma (PDAC).
  • FIG. 1 A Western blot of a dose response treatment of 2838c3 PD AC cells with G-l.
  • FIG. 1B Western blot of 2838c3 PDAC cells treated with a pulse or constant 500 nM dose of G-l.
  • FIGs. 1D-1G Western blot for p-RB, RB, and c-Myc on several PDAC cell lines.
  • FIG. 1A Western blot of a dose response treatment of 2838c3 PD AC cells with G-l.
  • FIG. 1B Western blot of 2838c3 PDAC cells treated with a pulse or constant 500 nM dose of G-l.
  • FIG. II Tumor volumes after G-l treatment.
  • FIG. 1J Tumor volumes over time of treatment groups.
  • FIG. 1K Survival curve of mice treated with vehicle or G-l, as well as aPD-l antibody or isotype antibody control (2A3). Significance between groups by the Log-Rank (Mantel-Cox) test is listed in the table in FIG. 1K.
  • FIG. 2 comprises a graph illustrating proliferation of Merkel cell carcinoma cells in the presence of varying concentrations of G-l.
  • the present invention relates to the unexpected discovery that estrogen and/or small molecule G-protein coupled receptor (GPCR) agonists (such as selective G protein-coupled estrogen receptor (GPER) agonists) can be used in combination with immunotherapy to treat and/or prevent pancreatic cancer, such as but not limited to K-Ras- driven pancreatic cancer.
  • GPCR G-protein coupled receptor
  • GPER selective G protein-coupled estrogen receptor
  • the combination of estrogen/GPCR agonists and immunotherapy is synergistic in nature, allowing for higher efficacy than the sum of thr efficacies that would be obtained with the separate administration of each therapeutic agent.
  • the combination of estrogen/GPCR agonists and immunotherapy allows for significant cure rates, while the individual administration of each therapeutic agent does not provide significant (or even measurable) increase in survival.
  • Pancreatic cancer can be subdivided in exocrine pancreatic cancers (which affect areas of the pancreas that produce digestive enzymes) and endocrine pancreatic cancers (which affect areas of the pancreas that produce hormones, and are rather rare as compared to the exocrine subtype).
  • Exocrine pancreatic cancers comprise pancreatic adenocarcinomas (which include invasive or ductal variants), acinar cell carcinomas, cystadenocarcinomas, pancreatoblastomas, adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas, undifferentiated carcinomas, undifferentiated carcinomas with osteoclast-like giant cells, solid pseudopapillary tumors, and pancreatic mucinous cystic neoplasms.
  • pancreatic adenocarcinomas which include invasive or ductal variants
  • acinar cell carcinomas cystadenocarcinomas
  • pancreatoblastomas pancreatoblastomas
  • adenosquamous carcinomas signet ring cell carcinomas
  • colloid carcinomas undifferentiated carcinomas
  • undifferentiated carcinomas with osteoclast-like giant cells solid pseudopapillary tumors
  • subjects at increased risk of pancreatic cancer can benefit from treatment with estrogen and/or a GPCR agonist (such as a selective GPER agonist).
  • a GPCR agonist such as a selective GPER agonist
  • a general subject can benefit from treatment with estrogen and/or a GPCR agonist (such as a selective GPER agonist), which acts as a preventive or maintenance treatment against future occurrences of pancreatic cancer, such as but not limited to K-Ras-driven pancreatic cancer.
  • current pancreatic cancer patients such as but not limited to K- Ras-driven pancreatic cancer patients, can benefit from treatment with estrogen and/or a GPCR agonist (such as a selective GPER agonist), either alone and/or in combination with immunotherapies.
  • a GPCR agonist such as a selective GPER agonist
  • the present invention relates to the unexpected discovery that estrogen and/or small molecule GPCR agonists can be used to treat and/or prevent Merkel cell carcinoma (MCC).
  • MCC Merkel cell carcinoma
  • MCC is a rare and highly aggressive skin cancer, which, in most cases, is caused by the Merkel cell polyomavirus (MCV).
  • MCC is also known as cutaneous APUDoma, primary neuroendocrine carcinoma of the skin, primary small cell carcinoma of the skin, or trabecular carcinoma of the skin. MCC occurs most often in Caucasians between 60 and 80 years of age, and its rate of incidence is about twice as high in males as in females. There are roughly 1,500 new cases of MCC diagnosed each year in the ETS. MCC is considered to be a form of neuroendocrine tumor.
  • Immunosuppression can profoundly increase the odds of developing MCC. That cancer occurs 30 times more often in people with chronic lymphocytic leukemia and 13.4 times more often in people with advanced HIV as compared to the general population. Solid organ transplant recipients have a lO-fold increased risk for MCC compared to the general population.
  • GPER agonists have significant activity against MCC.
  • MCC responds to GPER agonist at the same concentrations that are effective against melanoma, pancreas, and lung cancer cells.
  • MCC was recently shown to be highly responsive to anti -PD- 1 therapy (50% cured and 50% progress).
  • estrogen and/ GPCR agonists can be used in combination with immunotherapy to treat and/or prevent MCC. In other embodiments, that combination provides better outcomes (expressed as, for example, life expectancy and/or efficacy) that are superior to those observed with immunotherapy alone.
  • subjects at increased risk of MCC can benefit from treatment with estrogen and/or a GPCR agonist (such as a selective GPER agonist).
  • a general subject can benefit from treatment with estrogen and/or a GPCR agonist (such as a selective GPER agonist), which acts as a preventive or maintenance treatment against future occurrences of MCC.
  • current MCC patients can benefit from treatment with estrogen and/or a GPCR agonist (such as a selective GPER agonist), either alone and/or in combination with immunotherapies.
  • the term“about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, ⁇ 5%, ⁇ 1%, or ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined elsewhere herein, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, l-propoxy, 2-propoxy (or isopropoxy) and the higher homologs and isomers.
  • oxygen atom such as, for example, methoxy, ethoxy, l-propoxy, 2-propoxy (or isopropoxy) and the higher homologs and isomers.
  • a specific example is (Ci-C 3 )alkoxy, such as, but not limited to, ethoxy and methoxy.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, /f/V-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl.
  • a specific embodiment is (Ci-C 4 )alkyl, such as, but not limited to, ethyl, methyl, isopropyl, n- butyl, isobutyl, t-butyl, and cyclopropylmethyl.
  • A“disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.
  • a“disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.
  • Effective amount or“therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result or provides a therapeutic or prophylactic benefit. Such results may include, but are not limited to, anti-tumor activity as determined by any means suitable in the art.
  • endogenous refers to any material from or produced inside an organism, cell, tissue or system.
  • Estrogen or“oestrogen” as used herein refers to any substance, natural or synthetic (including analogues and derivatives of estrogen), that mimics the effect of the natural hormone, estrogen.
  • Types of estrogen include, but are not limited to, estrone (El), estradiol (E2), estriol (E3), estetrol (E4), l7P-estradiol, 27-hydroxy cholesterol,
  • dehydroepiandrosterone DHEA
  • 7-oxo-DHEA 7a-hydroxy-DHEA
  • l6a-hydroxy-DHEA 7P-hydroxyepiandrosterone
  • a 4 -androstenedione A 5 -androstenediol
  • 3a-androstanediol 3b- androstanediol
  • 2-hydroxyestrone l6-hydroxyestrone
  • estradiol cypionate estradiol valerate, estradiol acetate, estradiol benzoate
  • ethinyl estradiol (EE) mestranol, moxestrol, quinestrol, diethylstilbestrol benzestrol, dienestrol, dienestrol acetate, diethylstilbestrol dipropionate, fosfestrol, hexestrol, methestrol dipropionate, xenoestrogens, phytoestrogens, and
  • halo or“halogen” alone or as part of another substituent refers to, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • GPCR refers to G-protein coupled receptor.
  • GPER refers to a G protein-coupled estrogen receptor, which is a type of GPCR.
  • an“instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the compositions and methods of the invention.
  • the instructional material of the kit of the invention may, for example, be affixed to a container which contains the nucleic acid, peptide, and/or composition of the invention or be shipped together with a container which contains the nucleic acid, peptide, and/or composition.
  • the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
  • immune checkpoint inhibitor refers to a drug (such as a small molecule, peptide and/or antibody) that triggers an immune system attack on cancer cells.
  • immune checkpoint inhibitors include, but are not limited to, antibodies, PD-l inhibitors (i.e. Pembrolizumab, Nivolumab, anti-PD-l), PD-L1 inhibitors (i.e. Avelumab, Atezolizumab, anti-PD-Ll), CTLA-4 inhibitors (i.e.
  • Ipilimumab Ipilimumab, anti-B7-l/B7-2, anti- CTLA-4), Indoleamine (2, 3)-di oxygenase (IDO 1/2) inhibitors, B7 homolog 3 (B7-H3) inhibitors, lymphocyte activation gene 3 (LAG3) inhibitors, and TIGIT (T cell
  • immunoreceptor with Ig and ITIM domains targeting antibodies and agents.
  • “modified” as used herein is meant a changed state or structure of a molecule or cell of the invention.
  • Molecules may be modified in many ways, including chemically, structurally, and functionally.
  • Cells may be modified through the introduction of nucleic acids.
  • moduleating mediating a detectable increase or decrease in the level of a response in a subject compared with the level of a response in the subject in the absence of a treatment or compound, and/or compared with the level of a response in an otherwise identical but untreated subject.
  • the term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, preferably, a human.
  • parenteral administration of an immunogenic composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, or infusion techniques.
  • composition refers to a mixture of at least one compound useful within the invention with other chemical
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, intracranial, transdermal and topical administration.
  • the administration comprises topical administration.
  • the term“pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the composition, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term“pharmaceutically acceptable carrier” means a
  • composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the subject such that it may perform its intended function.
  • Such constructs are carried or transported from one
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil;
  • glycols such as propylene glycol
  • polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid;
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions.
  • The“pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
  • pharmaceutically acceptable salt refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and/or bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates (including hydrates) and clathrates thereof.
  • a“pharmaceutically effective amount,”“therapeutically effective amount” or“effective amount” of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered.
  • prevent means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such symptoms at the time the administering of an agent or compound commences.
  • Disease, condition and disorder are used interchangeably herein.
  • a first molecule preferentially binds to a second molecule (e.g., a particular receptor or enzyme), but does not necessarily bind only to that second molecule.
  • a second molecule e.g., a particular receptor or enzyme
  • A“subject” is intended to include living organisms in which an immune response can be elicited (e.g., mammals).
  • A“subject” or“patient,” as used therein, may be a human or non-human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
  • the subject is human.
  • a“substantially purified” cell is a cell that is essentially free of other cell types.
  • a substantially purified cell also refers to a cell that has been separated from other cell types with which it is normally associated in its naturally occurring state.
  • a population of substantially purified cells refers to a homogenous population of cells. In other embodiments, this term refers simply to cell that have been separated from the cells with which they are naturally associated in their natural state.
  • the cells are cultured in vitro. In yet other embodiments, the cells are not cultured in vitro.
  • “therapeutic” as used herein means a treatment and/or prophylaxis. A therapeutic effect is obtained by suppression, remission, or eradication of a disease state.
  • “topical administration” or“topical application” refers to a medication applied to body surfaces such as the skin or mucous membranes.
  • To“treat” a disease means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject.
  • the term“treatment” or“treating” is defined as the application or administration of a therapeutic agent, i.e., a composition useful within the invention (alone or in combination with another pharmaceutical agent), to a subject, or application or administration of a therapeutic agent to an isolated tissue or cell line from a subject (e.g., for diagnosis or ex vivo applications), who has a disease or disorder, a symptom of a disease or disorder or the potential to develop a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease or disorder, the symptoms of the disease or disorder or the potential to develop the disease or disorder.
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • UV refers to ultraviolet
  • the present invention contemplates the use of estrogen and/or other small molecules that bind to and activate a GPCR, such as the G protein-coupled estrogen receptor GPER. In certain embodiments, this induces cell signaling events that increase the differentiation state of the tumor cell. In other embodiments, this slows tumor cell proliferation, slows overall tumor growth, and renders tumor cells more visible to immune cells and/or susceptible to immunotherapy. In yet other embodiments, the present invention contemplates other molecules that serve as agonists of other GPCRs. Such molecules induce cell differentiation by engaging many of the same downstream pathways that are activated by GPER.
  • the compound, or a salt, solvate, tautomer, enantiomer or diastereoisomer thereof is at least one compound of formula (I):
  • R 2 is selected from the group consisting of C 1 -C 4 alkyl and Ci-C 4 haloalkyl (such as, but not limited to, -CF 3 );
  • bond a is a single or double bond, such that:
  • R 3 and R* are H
  • R 3 is selected from the group consisting of H, -OH, -OAc, and halo; * is selected from the group consisting of H, -OH, -OAc, and -S(o-nitrophenyl); or R 3 and R 4 combine to form a diradical selected from the group consisting of -CH 2 -, -0CH 2 0-, -0CH(CH 3 )0-, and -0C(CH 3 ) 2 0-;
  • R 5 is selected from the group consisting of H, benzyl, C 4 -C 4 alkyl, and acetyl;
  • s is selected from the group consisting of H, halo, -N0 2 , C 4 -C 4 alkyl, -CoCH, -CoC- Si(CH 3 ) 3 (or -CoC-TMS), -O-benzyl, -OH, -OAc, C 4 -C 4 alkoxy, -COOH, and - COO(C C 4 alkyl);
  • R 7 is selected from the group consisting of H, halo, -N0 2. C 4 -C 4 alkyl, -OH, -OAc, and C 4 -C 4 alkoxy;
  • R 9 is selected from the group consisting of H, halo, -N0 2 , C 4 -C 4 alkyl, -OH, -OAc, and C 4 -C 4 alkoxy,
  • Rio is selected from the group consisting of H, C 4 -C 4 alkyl, and halo; wherein each occurrence of benzyl is independently optionally substituted with at least one group selected from the group consisting of C 1 -C 4 alkyl, -OH, Ci-C 4 alkoxy, halo, and -N0 2.
  • the compound, or a salt, solvate, tautomer, enantiomer or diastereoisomer thereof is at least one compound of formula (1-1):
  • R 2 is Ci-C 4 alkyl
  • bond a is a single or double bond, such that:
  • R 3 and R* are H
  • R 3 and * are independently selected from the group consisting of H and -OH, or R 3 and R 4 combine to form a diradical selected from the group consisting of -OCH 2 0-, -OCH(CH 3 )0- and - 0C(CH 3 ) 2 0-;
  • R 5 is selected from the group consisting of H, benzyl and C 4 -C 4 alkyl
  • s is selected from the group consisting of H and halo
  • R 8 and R 9 are independently selected from the group consisting of H and C 4 -C 4 alkoxy, or R 8 and R 9 combine to form a diradical selected from the group consisting of -OCH 2 0-, - OCH(CH 3 )0- and -0C(CH 3 ) 2 0-.
  • the compound is not G-l. In other embodiments, the compound is G-l.
  • R 2 is selected from the group consisting of methyl, trifluoromethyl, ethyl, l-propyl, and 2-propyl. In other embodiments, R 2 is methyl or trifluoromethyl.
  • bond a is a double bond
  • R 3 and R 4 are H.
  • bond a is a single bond, and R 3 and R are independently selected from the group consisting of H and -OH. In other embodiments, bond a is a single bond, and R 3 and R 4 are H. In yet other embodiments, bond a is a single bond, and R 3 and R 4 are -OH. In yet other embodiments, bond a is a single bond, and R 3 and R 4 are -OH and cis to each other. In yet other embodiments, bond a is a single bond, and R 3 and R 4 are -OH and trans to each other.
  • bond a is a single bond, and R 3 and R 4 combine to form - 0C(CH 3 ) 2 0-.
  • R 5 is selected from the group consisting of H, benzyl, methyl, ethyl, 1 -propyl and 2-propyl. In certain embodiments, R 5 is selected from the group consisting of H, benzyl and methyl.
  • 5 is selected from the group consisting of H, F, Cl, Br and I.
  • R 5 is selected from the group consisting of H, Cl and Br.
  • R 8 and R 9 are independently selected from the group consisting of H and C 1 -C 4 alkoxy. In other embodiments, R 8 and R 9 are independently selected from the group consisting of H, methoxy, ethoxy, l-propoxy and 2-propoxy. In yet other embodiments, R 8 and R 9 are independently selected from the group consisting of H and methoxy.
  • R 8 and R 9 combine to form a diradical selected from the group consisting of -0CH 2 0-, -0(CH 2 ) 2 0-, -0CH(CH 3 )0- and -0C(CH 3 ) 2 0-.
  • the compound, or a salt, solvate, tautomer, enantiomer or diastereoisomer thereof is at least one selected from the group consisting of:
  • the compound, or a salt, solvate, tautomer, enantiomer or diastereoisomer thereof is at least one selected from the group consisting of:
  • the compound is Al. In other embodiments, the compound is A2. In yet other embodiments, the compound is A3. In yet other embodiments, the compound is A4. In yet other embodiments, the compound is A5. In yet other embodiments, the compound is A6. In yet other embodiments, the compound is A7. In yet other embodiments, the compound is A8. In yet other embodiments, the compound is A9. In yet other embodiments, the compound is A10. In yet other embodiments, the compound is Al 1. In yet other embodiments, the compound is A12. In yet other embodiments, the compound is A13. In yet other embodiments, the compound is A14. In yet other embodiments, the compound is A15.
  • the compound is not Al. In other embodiments, the compound is not A2. In yet other embodiments, the compound is not A3. In yet other embodiments, the compound is not A4. In yet other embodiments, the compound is not A5. In yet other embodiments, the compound is not A6. In yet other embodiments, the compound is not A7. In yet other embodiments, the compound is not A8. In yet other embodiments, the compound is not A9. In yet other embodiments, the compound is not A10. In yet other embodiments, the compound is not All. In yet other embodiments, the compound is not A12. In yet other embodiments, the compound is not A13. In yet other embodiments, the compound is not A14. In yet other embodiments, the compound is not A15.
  • the compound, or a salt, solvate, tautomer, enantiomer or diastereoisomer thereof is at least one selected from the group consisting of:
  • the compound is A16. In other embodiments, the compound is A17. In yet other embodiments, the compound is A18. In yet other embodiments, the compound is A19. In yet other embodiments, the compound is A20. In yet other
  • the compound is A21. In yet other embodiments, the compound is A22. In yet other embodiments, the compound is A23. In yet other embodiments, the compound is A24. In yet other embodiments, the compound is A25. In yet other embodiments, the compound is A26. In yet other embodiments, the compound is A27. In yet other embodiments, the compound is A28. In yet other embodiments, the compound is A29. In yet other
  • the compound is A30. In yet other embodiments, the compound is A31. In yet other embodiments, the compound is A32. In yet other embodiments, the compound is A33. In yet other embodiments, the compound is A34. In yet other embodiments, the compound is A35. In yet other embodiments, the compound is A36. In yet other embodiments, the compound is A37. In yet other embodiments, the compound is A38. In yet other embodiments, the compound is A39. In yet other embodiments, the compound is A40. In yet other embodiments, the compound is A41. In yet other embodiments, the compound is A42. In yet other embodiments, the compound is A43. In yet other embodiments, the compound is A44. In yet other embodiments, the compound is A45. In yet other embodiments, the compound is A46. In yet other embodiments, the compound is A47. In yet other
  • the compound is A48. In yet other embodiments, the compound is A49. In yet other embodiments, the compound is A50. In yet other embodiments, the compound is A51. In yet other embodiments, the compound is A52. In yet other embodiments, the compound is A53. In yet other embodiments, the compound is A54. In yet other embodiments, the compound is A55. In yet other embodiments, the compound is A56. In yet other embodiments, the compound is A48. In yet other embodiments, the compound is A49. In yet other embodiments, the compound is A50. In yet other embodiments, the compound is A51. In yet other embodiments, the compound is A52. In yet other embodiments, the compound is A53. In yet other embodiments, the compound is A54. In yet other embodiments, the compound is A55. In yet other embodiments, the compound is A56. In yet other
  • the compound is A57. In yet other embodiments, the compound is A58. In yet other embodiments, the compound is A59. In yet other embodiments, the compound is A60. In yet other embodiments, the compound is A61. In yet other embodiments, the compound is A62. In yet other embodiments, the compound is A63. In yet other embodiments, the compound is A64. In yet other embodiments, the compound is A65. In yet other embodiments,
  • the compound is A66. In yet other embodiments, the compound is A67. In yet other embodiments, the compound is A68. In yet other embodiments, the compound is A69. In yet other embodiments, the compound is A70. In yet other embodiments, the compound is A71. In yet other embodiments, the compound is A72. In yet other embodiments, the compound is A73. In yet other embodiments, the compound is A74. In yet other
  • the compound is A75. In yet other embodiments, the compound is A76. In yet other embodiments, the compound is A77. In yet other embodiments, the compound is A78. In yet other embodiments, the compound is A79. In yet other embodiments, the compound is A80. In yet other embodiments, the compound is A81. In yet other embodiments, the compound is A82. In yet other embodiments, the compound is A83. In yet other
  • the compound is A84. In yet other embodiments, the compound is A85. In yet other embodiments, the compound is A86. In yet other embodiments, the compound is A87. In yet other embodiments, the compound is A88. In yet other embodiments, the compound is A89. In yet other embodiments, the compound is A90. In yet other embodiments, the compound is A91. In yet other embodiments, the compound is A92. In yet other embodiments, the compound is A84. In yet other embodiments, the compound is A85. In yet other embodiments, the compound is A86. In yet other embodiments, the compound is A87. In yet other embodiments, the compound is A88. In yet other embodiments, the compound is A89. In yet other embodiments, the compound is A90. In yet other embodiments, the compound is A91. In yet other embodiments, the compound is A92. In yet other
  • the compound is A93. In yet other embodiments, the compound is A94. In yet other embodiments, the compound is A95. In yet other embodiments, the compound is A96. In yet other embodiments, the compound is A97. In yet other embodiments, the compound is A98. In yet other embodiments, the compound is A99. In yet other embodiments, the compound is A100. In yet other embodiments, the compound is A101. In yet other embodiments, the compound is A102. In yet other embodiments, the compound is A103. In yet other embodiments, the compound is A104.
  • the compound is not A16. In other embodiments, the compound is not A17. In yet other embodiments, the compound is not A18. In yet other embodiments, the compound is not A19. In yet other embodiments, the compound is not A20. In yet other embodiments, the compound is not A21. In yet other embodiments, the compound is not A22. In yet other embodiments, the compound is not A23. In yet other embodiments, the compound is not A24. In yet other embodiments, the compound is not A25. In yet other embodiments, the compound is not A26. In yet other embodiments, the compound is not A27. In yet other embodiments, the compound is not A28. In yet other embodiments, the compound is not A29.
  • the compound is not A30. In yet other embodiments, the compound is not A31. In yet other embodiments, the compound is not A32. In yet other embodiments, the compound is not A33. In yet other embodiments, the compound is not A34. In yet other embodiments, the compound is not A35. In yet other embodiments, the compound is not A36. In yet other embodiments, the compound is not A37. In yet other embodiments, the compound is not A38. In yet other embodiments, the compound is not A39. In yet other embodiments, the compound is not A40. In yet other embodiments, the compound is not A41. In yet other embodiments, the compound is not A42. In yet other embodiments, the compound is not A43.
  • the compound is not A44. In yet other embodiments, the compound is not A45. In yet other embodiments, the compound is not A46. In yet other embodiments, the compound is not A47. In yet other embodiments, the compound is not A48. In yet other embodiments, the compound is not A49. In yet other embodiments, the compound is not A50. In yet other embodiments, the compound is not A51. In yet other embodiments, the compound is not A52. In yet other embodiments, the compound is not A53. In yet other embodiments, the compound is not A54. In yet other embodiments, the compound is not A55. In yet other embodiments, the compound is not A56. In yet other embodiments, the compound is not A57.
  • the compound is not A58. In yet other embodiments, the compound is not A59. In yet other embodiments, the compound is not A60. In yet other embodiments, the compound is not A61. In yet other embodiments, the compound is not A62. In yet other embodiments, the compound is not A63. In yet other embodiments, the compound is not A64. In yet other embodiments, the compound is not A65. In yet other embodiments, the compound is not A66. In yet other embodiments, the compound is not A67. In yet other embodiments, the compound is not A68. In yet other embodiments, the compound is not A69. In yet other embodiments, the compound is not A70. In yet other embodiments, the compound is not A71.
  • the compound is not A72. In yet other embodiments, the compound is not A73. In yet other embodiments, the compound is not A74. In yet other embodiments, the compound is not A75. In yet other embodiments, the compound is not A76. In yet other embodiments, the compound is not A77. In yet other embodiments, the compound is not A78. In yet other embodiments, the compound is not A79. In yet other embodiments, the compound is not A80. In yet other embodiments, the compound is not A81. In yet other embodiments, the compound is not A82. In yet other embodiments, the compound is not A83. In yet other embodiments, the compound is not A84. In yet other embodiments, the compound is not A85.
  • the compound is not A86. In yet other embodiments, the compound is not A87. In yet other embodiments, the compound is not A88. In yet other embodiments, the compound is not A89. In yet other embodiments, the compound is not A90. In yet other embodiments, the compound is not A91. In yet other embodiments, the compound is not A92. In yet other embodiments, the compound is not A93. In yet other embodiments, the compound is not A94. In yet other embodiments, the compound is not A95. In yet other embodiments, the compound is not A96. In yet other embodiments, the compound is not A97. In yet other embodiments, the compound is not A98. In yet other embodiments, the compound is not A99.
  • the compound is not A100. In yet other embodiments, the compound is not A101. In yet other embodiments, the compound is not A102. In yet other embodiments, the compound is not A103. In yet other embodiments, the compound is not A104.
  • the compound of the invention or a salt, solvate, tautomer, enantiomer or diastereoisomer thereof, is at least one compound selected from the group
  • the compound is not A105. In other embodiments, the compound is not A106.
  • the compound of the invention or a salt, solvate, tautomer, enantiomer or diastereoisomer thereof, other embodiments, the compound is not A107.
  • the compound is at least one selected from the group consisting of:
  • Gl or G-l (rel-l-[4-(6-bromo-l,3-benzodioxol-5-yl)-3aR,4S,5,9bS-tetrahydro-3H-
  • CMPD4 (rel-l-((3aS,4R,9bR)-5-benzyl-4-(6-bromobenzo[d][l,3]dioxol-5-yl)-3a,4,5,9b-
  • CMPD5 (rel-l-((3aS,4R,9bR)-4-(2-bromophenyl)-3a,4,5,9b-tetrahydro-3H-
  • CMPD6 (rel-l-((3aS,4R,9bR)-4-(6-bromobenzo[d][l,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-
  • CMPD7 (rel-l-((3aS,4R,9bR)-4-(2-bromo-4,5-dimethoxyphenyl)-3a,4,5,9b-tetrahydro-3H- cyclopenta[c]quinolin-8-yl)ethan-l-one)
  • CMPD8 (rel-l-((3aS,4R,9bR)-4-(6-chlorobenzo[d][l,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-
  • CMPD9 (rel-l-((6R,6aS,7aS,l0aR,l0bR)-6-(6-bromobenzo[d][l,3]dioxol-5-yl)-9,9- dimethyl-6, 6a, 7, 7a, l0a,l0b-hexahydro-5H-[l,3]dioxolo[4’, 5’ :3,4]cyclopenta[l,2-c]quinolin-
  • CMPD10 (rel-l-((lR,2S,3aS,4R,9bR)-4-(6-bromobenzo[d][l,3]dioxol-5-yl)-l,2-dihydroxy- 2,3,3a,4,5,9b-hexahydro-lH-cyclopenta[c]quinolin-8-yl)ethan-l-one):
  • CMPD11 (rel-l-((3aS,4R,9bR)-4-(2-bromo-4,5-dimethoxyphenyl)-2,3,3a,4,5,9b-hexahydro-
  • the compound of the invention or a salt, solvate, tautomer, enantiomer or diastereoisomer thereof, is at least one compound of formula (II): wherein:
  • R 2 is C 1 -C 4 alkyl
  • R5 is selected from the group consisting of H, benzyl and C 1 -C 4 alkyl
  • R 8 and R 9 are independently selected from the group consisting of H and C1-C4 alkoxy, or R 8 and R9 combine to form a diradical selected from the group consisting of -0CH 2 0-, - 0CH(CH 3 )0- and -0C(CH 3 ) 2 0-.
  • the compound of formula (II) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • CMPD12 (rel-l-((4S,5aS,6R,llaR)-4,5,5a,6,ll,lla-hexahydro-4,6-methano[l,3]
  • the compound useful within the methods of the invention, or a salt, solvate, enantiomer or diastereoisomer thereof is at least one GPER agonist recited in U.S. Patent Application Publications No. US 2008/0167334 and US 2011/0092533, all of which are incorporated herein in their entireties by reference:
  • X N-, O, S, or N-R, with the proviso that when X is N-R and R is a bond, N together with R 1 forms a 5- to 7-membered optionally substituted heterocyclic group;
  • R is a bond, H, -OH, -N0 2 , optionally substituted Ci-C 6 hydrocarbyl (such as optionally substituted alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted -C(0)-(Ci-C 6 ) alkyl (amide), optionally substituted -C(0)-0-(Ci-C 6 ) alkyl (urethane), optionally substituted -C(0)-NH(Ci- C 6 ) alkyl (urea), optionally substituted -C(0)-N(Ci-C 6 )dialkyl, optionally substituted -C(O)- NH(aryl), optionally substituted -C(0)-N(diaryl), optionally substituted -C(O)- NH(heteroaryl), optionally substituted -C(0)-N(diheteroaryl), optionally substituted -C(O)- NH(heteroaryl), optional
  • R 1 , R 2 and R 5 are each independently selected from H, -OH, -N0 2 , halogen, Ci-C 6 optionally substituted carboxylic acid group, optionally substituted 0-(Ci-C 6 )alkyl, optionally substituted Ci-C 6 hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted -C(0)-(Ci-C 6 ) alkyl (ketone), optionally substituted -C(0)-0-(Ci-C 6 ) alkyl (ester), optionally substituted 0-C(0)-(Ci-C 6 ) alkyl (ester), optionally substituted -C(0)-NH(Ci-C 6 ) alkyl (urea), optionally substituted - C(0)-N(Ci-C 6 )dialkyl, optionally substituted -C(0)-NH(aryl), optionally substituted -C(O)- N(diaryl), optionally substitute
  • R 3 and R 4 are each independently selected from H, -OH, -N0 2 , halogen, Ci-C 6 optionally substituted carboxylic acid group, optionally substituted 0-(Ci-C 6 )alkyl, optionally substituted Ci-C 6 hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted -C(0)-(Ci-C 6 ) alkyl (ketone), optionally substituted -C(0)-0-(Ci-C 6 ) alkyl (ester), optionally substituted 0-C(0)-(Ci-C 6 ) alkyl (ester), optionally substituted -C(0)-NH(Ci-C 6 ) alkyl (urea), optionally substituted - C(0)-N(Ci-C 6 )dialkyl, optionally substituted -C(0)-NH(aryl), optionally substituted -C(O)- N(diaryl), optionally substituted -C
  • R 6 and R 7 are each independently absent or are selected from H, -OH, -N0 2 , halogen, Ci-C 6 optionally substituted carboxylic acid group, optionally substituted 0-(Ci-C 6 )alkyl, optionally substituted Ci-C 6 hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted -C(0)-(Ci-C 6 ) alkyl (ketone), optionally substituted -C(0)-0-(Ci-C 6 ) alkyl (ester), optionally substituted O-C(O)- (Ci-C 6 ) alkyl (ester), optionally substituted -C(0)-NH(Ci-C 6 ) alkyl (urea), optionally substituted -C(0)-N(Ci-C 6 )dialkyl, optionally substituted -C(0)-NH(aryl), optionally substituted -C(0)-N(diaryl), optionally substituted
  • R 7" is absent, H, -OH, halogen, optionally substituted 0-(Ci-C 6 )alkyl, optionally substituted Ci-C 6 hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted -C(0)-(Ci-C 6 ) alkyl (ketone), optionally substituted -C(0)-0-(Ci-C 6 ) alkyl (ester), optionally substituted 0-C(0)-(Ci-C 6 ) alkyl (ester), optionally substituted -C(0)-NH(Ci-C 6 ) alkyl (urea), optionally substituted - C(0)-N(Ci-C 6 )dialkyl, optionally substituted -C(0)-NH(aryl), optionally substituted -C(O)- N(diaryl), optionally substituted -C(0)-NH(heteroaryl), optionally substituted -C(O)- N(di
  • R 8 is absent (when the carbon to which R 8 is attached and the carbon to which R 6 is attached form an optional double bond), H, C3 ⁇ 4 or CH 2 CH 3 ;
  • R 10 , R 11 , R 12 and R 13 are each independently H, -OH, -NO 2 , halogen, Ci-C 6 optionally substituted carboxylic acid group, optionally substituted 0-(Ci-C 6 )alkyl, optionally substituted Ci-C 6 hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted -C(0)-(Ci-C 6 ) alkyl (ketone), optionally substituted -C(0)-0-(Ci-C 6 ) alkyl (ester), optionally substituted 0-C(0)-(Ci-C 6 ) alkyl (ester), optionally substituted -C(0)-NH(Ci-C 6 ) alkyl (urea), optionally substituted - C(0)-N(Ci-C 6 )dialkyl, optionally substituted -C(0)-NH(aryl), optionally substituted -C(O)- N(diaryl), optionally
  • R 14 is H, -OH, -NO 2 , halogen, Ci-C 6 optionally substituted carboxylic acid group, optionally substituted 0-(Ci-C 6 )alkyl, optionally substituted Ci-C 6 hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted -C(0)-(Ci-C 6 ) alkyl (ketone), optionally substituted -C(0)-0-(Ci-C 6 ) alkyl (ester), optionally substituted 0-C(0)-(Ci-C 6 ) alkyl (ester), optionally substituted - C(0)-NH(C I -C 6 ) alkyl (urea), optionally substituted -C(0)-N(Ci-C 6 )dialkyl, optionally substituted -C(0)-NH(aryl), optionally substituted -C(0)-N(diaryl), optionally substituted - C(0)-NH(heteroaryl
  • the compound of the invention is at least one GPER agonist recited in PCT Patent Application No. WO 2016/014847, which is incorporated herein in its entirety by reference:
  • Ring A is an aromatic or heteroaromatic five or six membered ring containing one or more heteroatom such as N, O, or S;
  • Ri is independently selected from S0 2 NH 2 , S0 2 NR a R b , COOH, CONH 2 and
  • each occurrence of R a and R b is independently selected from H, alkyl (Ci-C 6 ), alkenyl (C 2 -C 6 ), alkynyl (C 2 -C 6 ), alkoxy (C 2 -C 6 ), cycloalkyl (C 3 -C 7 ), alkylthio, alkylaryl, and aromatic and hetroaromatic rings.
  • the aromatic and heteroaromatic rings can be further substituted with electron withdrawing and donating groups.
  • R a and R b can form a cyclic ring (C 3 -C 7 ) or an aromatic ring optionally containing one or more heteroatoms.
  • Such aromatic rings can be further substituted with electron withdrawing groups such as halogens, -COOH, -CN, -NO 2 and the like, or electron donating groups such as alkyl groups;
  • R 2 is H, halogen, or a heteroatom such as N, O, or S;
  • Ring A is an aromatic or heteroaromatic ring (5 or 6 membered);
  • Ring B is a six membered saturated or aromatic ring containing N at the indicated position.
  • the nitrogen of ring B optionally can be substituted with an alkyl, aryl, or alkaryl substituent;
  • Ring C is an independently a substituted or unsubstituted carbocyclic ring, bicyclic ring, aromatic ring, fused aromatic rings, or a heteroaromatic ring. Additionally, when it is a carbocyclic ring, it may contain one or more double bonds and one or more heteroatoms such as N, O, or S. It may also have an a-b unsaturated ketone function;
  • R 3 is selected independently from H, halogen, -OH, CN, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (Ci-C 6 ) alkoxy, (C 3 -C 7 ) cycloalkyl, (Ci-C 6 ) alkylthio, NR a R b , R a R b or haloalkyl (e.g., CF 3 ).
  • each occurrence of R a and R b is independently hydrogen or (Ci-C 6 ) alkyl, or R a and R b form a saturated or unsaturated heterocyclic ring containing from 3-7 ring atoms, which ring may optionally contain another heteroatom selected from N, O, and S, and may be optionally substituted by from 1-3 groups which may be the same or different and are selected from (C 1 -C 4 ) alkyl, phenyl, and benzyl; and m is 1-4;
  • Rings B and C are in certain embodiments cis fused
  • Rings D and B is directly connected or connected through a spacer (C1-C2). When connected directly, they can be cis or trans with respect to the fusion of Ring B and C.
  • Ring D is an aromatic or heteroaromatic ring containing one or more heteroatoms such as N, O, or S. It can be optionally substituted with R 5 and R 6 groups selected independently, or with - ReR 5 or R5R6;
  • R5 is independently selected from H, halogen, electron donating groups, and electron withdrawing groups such as alkyl, haloalkyl, alkoxy, -N0 2 , -SF 5 , -CN, and the like;
  • R c is alkyl, branched alkyl (C1-C10), alkoxy, alkylamino, acyl, alkynyl (Ci-C 8 ) or alkenyl (Ci-C 6 ).
  • Ri is selected from the group consisting of carboxyl, carboxamide, carboxyalkyl, carboxyaryl, cyano, nitro, hydroxyl, sulfonyl, sulfonamide, alkylsulfonamide, arylsulfonamide, alkylsulfonyl, aralkylsulfonamide,
  • Ri is sulfonamide, alkylsulfonamide, or arylsulfonamide.
  • R 2 can be a 3-, 4-, 5-, or 6-membered saturated or aromatic carbon ring or ring system optionally containing one or two heteroatoms selected from N, O, and S, the ring or ring system optionally substituted with one or more substituents selected from the group consisting of cyano, halo, acyl, acyloxy, alkyl, alkoxy, heteroalkyl, alkylester, alkylamido, alkylamino, aryl, aryloxy, arylalkyl, arylester, azido, alkylhalo, alkenyl, alkynyl, alkyl ether, nitro, thiohalo, and thiocyano.
  • substituents selected from the group consisting of cyano, halo, acyl, acyloxy, alkyl, alkoxy, heteroalkyl, alkylester, alkylamido, alkylamino, aryl, aryloxy, arylal
  • R 3 can be H, or a Ci-C 5 alkyl or cycloalkyl group optionally substituted with one or more of cyano, nitro, and one or more aromatic or heteroaromatic groups containing N, O, or S.
  • a and D can be independently selected from CH, CH 2 , N, and O, and the bond joining them is a single or double bond as appropriate for the selected atoms.
  • X, Y, and Z are independently selected from no atom (i.e., they are absent), CH, C-halogen,
  • R 2 is a substituent represented by -R d R c Rf or by -R d COR e Rf; wherein R d, R e , and R f are independently selected from a 3-, 4-, 5-, or 6-membered saturated or aromatic carbon ring or ring system optionally containing one or two heteroatoms selected from N, O, and S, the ring or ring system optionally substituted with one or more substituents selected from the group consisting of cyano, halo, acyl, acyloxy, alkyl, alkoxy, heteroalkyl, alkylester, alkylamido, alkylamino, aryl, aryloxy, arylalkyl, arylester, azido, alkylhalo, alkenyl, alkynyl, alkyl ether, nitro, thiohalo, and thiocyano;
  • the compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the ( R ) or (S) configuration.
  • compounds described herein are present in optically active or racemic forms.
  • the compounds described herein encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a compound illustrated herein by the racemic formula further represents either of the two enantiomers or mixtures thereof, or in the case where two or more chiral center are present, all diastereomers or mixtures thereof.
  • the compounds of the invention exist as tautomers. All tautomers are included within the scope of the compounds recited herein.
  • Compounds described herein also include isotopically labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 ⁇ 4 U C, 13 C, 14 C, 36 Cl, 18 F, 123 1, 125 I, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, and 35 S. In certain embodiments, substitution with heavier isotopes such as deuterium affords greater chemical stability.
  • Isotopically labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the invention further provides pharmaceutical compositions comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for inhalational, oral, rectal, vaginal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, intracranial, or intravenous administration.
  • the pharmaceutical compositions of the invention comprise at least one additional anticancer agent and at least one compound of the invention.
  • additional anticancer agents include, but are not limited to, chemotherapy, and immune checkpoint inihibitors.
  • chemotherapy include, but are not limited to, a HD AC, temozolomide, dacarbazine (DTIC), vemurafenib, dabrafenib and trametinib.
  • DTIC dacarbazine
  • checkpoint inhibitors include, but are not limited to, PD-l inhibitors (i.e.
  • immunoreceptor with Ig and ITIM domains targeting antibodies and agents.
  • kits useful within any of the methods of the invention described herein comprise components useful in any of the methods described herein, one or more containers (e.g., test tube, cell culture dish, cell culture plate, cell culture flask, cell culture bag) for containing a component of any of the embodiments of the invention described elsewhere herein, and instructional materials.
  • containers e.g., test tube, cell culture dish, cell culture plate, cell culture flask, cell culture bag
  • the compounds described herein may form salts with acids or bases, and such salts are included in the present invention.
  • the term“salts” embraces addition salts of free acids or bases that are useful within the methods of the invention.
  • pharmaceutically acceptable salt refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications.
  • the salts are pharmaceutically acceptable salts.
  • Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the invention.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4- hydroxybenzoic, phenylacetic, mandelic, embonic (or pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, sulfanilic, 2-hydroxyethanesulfonic, trifluoromethanesulfonic, p-toluenesulfonic, cyclohexylaminosulfonic, stearic, alginic, b- hydroxybutyric
  • Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, ammonium salts and metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene- diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N- methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • the invention provides a method of treating or preventing pancreatic cancer, such as but not limited to K-Ras-driven pancreatic cancer, in a subject.
  • the method comprises administering to the subject in need thereof a therapeutically effective amount of estrogen and/or a GPCR agonist and a therapeutically effective amount of immunotherapy, such as but not limited to an immune checkpoint inhibitor.
  • the pancreatic cancer comprises pancreatic adenocarcinoma, acinar cell carcinoma, cystadenocarcinoma, pancreatoblastoma, adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, solid pseudopapillary tumor, and/or pancreatic mucinous cystic neoplasm.
  • the invention provides a method of treating or preventing MCC in a subject.
  • the method comprises administering to the subject in need thereof a therapeutically effective amount of estrogen and/or a GPCR agonist (such as, for example, a GPER agonist).
  • a GPCR agonist such as, for example, a GPER agonist
  • the subject is further administered a therapeutically effective amount of immunotherapy, such as but not limited to an immune checkpoint inhibitor.
  • the GPCR is GPER.
  • the GPER agonist comprises G-l.
  • the GPER agonist is selected from the group consisting of estradiol (E2), tamoxifen, fulvestrant, and raloxifene (also known as 6-hydroxy- 2-(4-hydroxyphenyl)-benzothiophen-3-yl]-[4-[2-(l-piperidyl)ethoxy]phenyl]-methanone).
  • the estrogen is any substance, natural or synthetic, that mimics the effect of the natural hormone, estrogen.
  • estrogen contemplated within the invention examples include, but are not limited to, estrone (El), estradiol (E2), estriol (E3), estetrol (E4), l7P-estradiol, 27-hydroxy cholesterol, dehydroepiandrosterone (DHEA), 7-oxo- DHEA, 7a-hydroxy-DHEA, l6a-hydroxy-DHEA, 7P-hydroxyepiandrosterone, D 4 - androstenedione, A 5 -androstenediol, 3a-androstanediol, 3P-androstanediol, 2-hydroxyestrone, 16-hydroxy estrone, estradiol cypionate, estradiol valerate, estradiol acetate, estradiol benzoate, ethinyl estradiol (EE), mestranol, moxestrol, quinestrol, diethylstilbestrol benzestrol, dienestrol, die
  • the estrogen and/or GPCR agonist is administered to the subject as a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.
  • immune checkpoint inhibitors include, but are not limited to, PD-l inhibitors (i.e. Pembrolizumab, Nivolumab, anti-PD-l), PD-L1 inhibitors (i.e. Avelumab, Atezolizumab, anti-PD-Ll), CTLA-4 inhibitors (i.e. Ipilimumab, anti-B7-l/B7-2, anti- CTLA-4), Indoleamine (2, 3)-di oxygenase (IDO 1/2) inhibitors, B7 homolog 3 (B7-H3) inhibitors, lymphocyte activation gene 3 (LAG3) inhibitors, and TIGIT (T cell
  • PD-l inhibitors i.e. Pembrolizumab, Nivolumab, anti-PD-l
  • PD-L1 inhibitors i.e. Avelumab, Atezolizumab, anti-PD-Ll
  • CTLA-4 inhibitors i.e. Ipilimumab, anti-B7-l
  • the immune checkpoint inhibitor is co-administered or co-formulated with the estrogen or GPCR agonist.
  • the estrogen or GPCR agonist is administered to the subject by an inhalational, oral, rectal, vaginal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, intracranial, or intravenous route of
  • the estrogen or GPCR agonist is the only anticancer agent administered to the subject. In yet other embodiments, the estrogen or GPCR agonist is the only anticancer agent administered to the subject in an amount sufficient to treat or prevent the cancer in the subject.
  • the subject is a mammal. In yet other embodiments, the mammal is human.
  • compositions of the invention will vary, depending upon the identity, size, and condition of the subject treated.
  • the composition may comprise between about 0.005% and about 100% (w/w) of the active agent, or any fractions or multiples thereof.
  • the pharmaceutical compositions useful for practicing the method of the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day, such as for example 1-50 mg/kg/day.
  • the pharmaceutical compositions useful for practicing the method of the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day, such as for example 1-50 mg/kg/day.
  • the pharmaceutical compositions useful for practicing the method of the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day, such as for example 1-50 mg/kg/day.
  • the pharmaceutical compositions useful for practicing the method of the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day, such as for example 1-50 mg/kg/day.
  • the pharmaceutical compositions useful for practicing the method of the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day, such as for example 1-50 mg/kg/day.
  • compositions useful for practicing the invention may be administered to deliver a dose of between 1 ng/kg/day and 1,000 mg/kg/day.
  • composition comprising a compound contemplated within the invention can be administered to a mammal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less.
  • the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
  • a 0.5-5 mg per day dose may be initiated on Monday with a first subsequent 0.5-5 mg per day dose administered on Wednesday, a second subsequent 0.5-5 mg per day dose administered on Friday, and so on.
  • the frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the animal, and so forth.
  • compositions are generally suitable for administration to animals of all sorts.
  • compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the
  • compositions of the invention include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.
  • compositions comprising a compound contemplated within the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound contemplated within the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • the administration comprises topical administration.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g ., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g. , other analgesic agents.
  • additional ingredients include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents;
  • dispersing or wetting agents emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials.
  • additional ingredients that may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed. (1985, Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA), which is incorporated herein by reference.
  • stratum corneum layer of the epidermis An obstacle for topical administration of pharmaceuticals is the stratum corneum layer of the epidermis.
  • the stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes cornified and living cells.
  • One of the factors that limit the penetration rate (flux) of a compound through the stratum corneum is the amount of the active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance applied per unit of area of the skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and in turn the greater the diffusion force of the active substance through the skin. Therefore, a formulation containing a greater concentration of the active substance is more likely to result in penetration of the active substance through the skin, and more of it, and at a more consistent rate, than a formulation having a lesser concentration, all other things being equal.
  • Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions.
  • Such formulations may be applied to the skin directly or through the use of swabs, applicators, spatulas and the like, as well as in the form of transdermal patches.
  • the patch minimizes loss of pharmaceuticals through washing, friction, scratching and/or rubbing of the skin.
  • the patch increases absorption of the pharmaceutical through the skin, while minimizing the exposure of the skin to the pharmaceutical.
  • Enhancers of permeation may be used. These materials increase the rate of penetration of drugs across the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethylsulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxy diglycol, laurocapram,
  • compositions of the invention may contain liposomes.
  • the composition of the liposomes and their use are known in the art (for example, U.S. Patent No. 6,323,219).
  • Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
  • parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.
  • the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
  • sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
  • the period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.
  • the compounds may be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compounds.
  • the compounds useful within the methods of the invention may be administered in the form of microparticles, for example by injection, or in the form of wafers or discs by implantation.
  • the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
  • pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, about 10 minutes, or about 1 minute and any or all whole or partial increments thereof after drug administration after drug administration.
  • rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, about 10 minutes, or about 1 minute and any and all whole or partial increments thereof after drug administration.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g ., nitrogen atmosphere, and reducing/oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
  • FIG. 1 A 2838c3 PDAC cells were treated with a pulse or constant 500 nM dose of G-l, and a Western blot of the dose response treatment is illustrated in FIG. 1B.
  • FIG. 1D-1G illustrate Western blots for p-RB, RB, and c-Myc on several PDAC cell lines.
  • FIG. II illustrates tumor volumes after G-l treatment.
  • FIG. 1 J illustrates tumor volumes over time of treatment groups.
  • FIG. 1K illustrates a survival curve of mice treated with vehicle or G-l, as well as aPD-l antibody or isotype antibody control (2A3). Significance between groups by the Log-Rank (Mantel-Cox) test is listed in the table in FIG. 1K.
  • FIG. 2 illustrates proliferation of Merkel cell carcinoma cells in the presence of varying concentrations of G-l .

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Abstract

La présente invention concerne des composés, des compositions et des procédés qui sont utiles pour prévenir ou traiter certains types de cancer chez un sujet. Dans certains modes de réalisation, les composés comprennent des oestrogènes (y Compris des dérivés d'oestrogènes ou des analogues) et/ou un agoniste sélectif de GPER.
PCT/US2018/065708 2017-12-14 2018-12-14 Composés et compositions pour la prévention et/ou le traitement du cancer Ceased WO2019118855A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4319881A4 (fr) * 2021-04-08 2025-08-27 Linnaeus Therapeutics Inc Variations oncologiques associées au cancer et méthodes de traitement

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US5571534A (en) * 1991-12-10 1996-11-05 Orion-Yhtyma Oy Drug formulations for parenteral use
US20080167334A1 (en) * 2005-08-04 2008-07-10 Prossnitz Eric R Compounds for binding to ERalpha/beta and GPR30, methods of treating disease states and conditions mediated through these receptors and identification thereof
US20150218274A1 (en) * 2014-01-31 2015-08-06 Novartis Ag Antibody molecules to tim-3 and uses thereof
WO2016137985A1 (fr) * 2015-02-26 2016-09-01 Merck Patent Gmbh Inhibiteurs de pd-1/pd-l1 pour le traitement du cancer

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
US5571534A (en) * 1991-12-10 1996-11-05 Orion-Yhtyma Oy Drug formulations for parenteral use
US20080167334A1 (en) * 2005-08-04 2008-07-10 Prossnitz Eric R Compounds for binding to ERalpha/beta and GPR30, methods of treating disease states and conditions mediated through these receptors and identification thereof
US20150218274A1 (en) * 2014-01-31 2015-08-06 Novartis Ag Antibody molecules to tim-3 and uses thereof
WO2016137985A1 (fr) * 2015-02-26 2016-09-01 Merck Patent Gmbh Inhibiteurs de pd-1/pd-l1 pour le traitement du cancer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4319881A4 (fr) * 2021-04-08 2025-08-27 Linnaeus Therapeutics Inc Variations oncologiques associées au cancer et méthodes de traitement

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