WO2016025652A1 - Combinaisons d'un inhibiteur de erk et d'un modulateur de la voie bcl-2 et méthodes associées - Google Patents

Combinaisons d'un inhibiteur de erk et d'un modulateur de la voie bcl-2 et méthodes associées Download PDF

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WO2016025652A1
WO2016025652A1 PCT/US2015/044932 US2015044932W WO2016025652A1 WO 2016025652 A1 WO2016025652 A1 WO 2016025652A1 US 2015044932 W US2015044932 W US 2015044932W WO 2016025652 A1 WO2016025652 A1 WO 2016025652A1
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cancer
compound
abt
bcl
mutated
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PCT/US2015/044932
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English (en)
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Ida ARONCHIK
Carmen Maria BARNES
Gordon L. BRAY
Ellen H. Filvaroff
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Celgene Avilomics Research, Inc.
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Publication of WO2016025652A1 publication Critical patent/WO2016025652A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with one or both of ERKl and ERK2 protein kinase.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
  • the processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells.
  • the MAPK or Raf-Mek-ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
  • ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase.
  • Activation of the ERK occurs via a cascade of phosphorylation events that begins with activation of Ras.
  • Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase.
  • Raf Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates one or both of ERKl and ERK2.
  • MEK1/2 When activated, one or both of ERKl and ERK2 phosphorylates several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation.
  • the ERK/MAPK pathway is one of the most important for cell proliferation, and human tumor data suggest that the ERK/MAPK pathway is frequently activated in many tumors.
  • Ras genes which are upstream of one or both of ERKl and ERK2, are mutated in several cancers including colorectal, melanoma, breast, lung, and pancreatic tumors.
  • High Ras activity is accompanied by elevated ERK activity in many human tumors.
  • activating mutations of BRAF a serine- threonine kinase of the Raf family, are associated with increased RAF, MEK, and ERK kinase activity.
  • Tumors types with the most frequent mutations in BRAF include melanomas (60%), thyroid cancers (greater than 40%) and colorectal cancers.
  • the present invention provides methods of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ERKl and ERK2 comprising administering to a patient in need thereof an inhibitor of one or both of ERK 1 and ERK2 in combination with a Bcl-2 (B-cell lymphoma 2) pathway modulator.
  • the inhibitor of one or both of ERKl and ERK2 is Compound 1 (N- (2-((2-(2-methoxy-5-methylpyridin-4-yl)amino)-5-(trifluorome
  • FIGs 1A, IB and 1C depict NCI-H460 Lung Cancer Cell Line: Lung cells were treated with a 9-point dose dilution of ABT-199 or ABT-263, Compound 1, or both, ranging from 1.52 nM to 10000.00 nM and DMSO vehicle control.
  • Fig. 1A dose response to Compound 1 (trend line with circles);
  • Fig. IB dose response with ABT-199 (trend line with circles) or ABT-263 (trend line with triangles);
  • Fig. 1C combination treatment with Compound 1 and ABT-199 (trend line with circles) and combination treatment with Compound 1 and ABT-263 (trend line with triangles).
  • FIGs 2A, 2B and 2C depict NCI-H727 Lung Cancer Cell Line: Lung cells were treated with a 9-point dose dilution of ABT-199 or ABT-263, Compound 1, or both, ranging from 1.52 nM to 10000.00 nM and DMSO vehicle control.
  • Fig. 2A dose response to Compound 1 (trend line with circles);
  • Fig. 2B dose response with ABT-199 (trend line with circles) or ABT-263 (trend line with triangles);
  • Fig. 2C combination treatment with Compound 1 and ABT-199 (trend line with circles) and combination treatment with Compound 1 and ABT-263 (trend line with triangles).
  • FIGs 3A, 3B and 3C depict NCI-H522 Lung Cancer Cell Line: Lung cells were treated with a 9-point dose dilution of ABT-199 or ABT-263, Compound 1, or both, ranging from 1.52 nM to 10000.00 nM and DMSO vehicle control.
  • Fig. 3 A dose response to Compound 1 (trend line with circles);
  • Fig. 3B dose response with ABT-199 (trend line with circles) or ABT-263 (trend line with triangles);
  • Fig. 3C combination treatment with Compound 1 and ABT-199 (trend line with circles) and combination treatment with Compound 1 and ABT-263 (trend line with triangles).
  • FIGs 4A, 4B and 4C depict NCI-H1755 Lung Cancer Cell Line: Lung cells were treated with a 9-point dose dilution of ABT-199 or ABT-263, Compound 1, or both, ranging from 1.52 nM to 10000.00 nM and DMSO vehicle control.
  • Fig. 4A dose response to Compound 1 (trend line with circles);
  • Fig. 4B dose response with ABT-199 (trend line with circles) or ABT-263 (trend line with triangles);
  • Fig. 4C combination treatment with Compound 1 and ABT-199 (trend line with circles) and combination treatment with Compound 1 and ABT-263 (trend line with triangles).
  • Figure 5 depicts a graph showing tolerability of combination treatment with Compound 1 and ABT-263 in nine female nu/nu mice over five days.
  • Figure 6 depicts a graph showing the maximum effect (Emax) of Compound 1 with ABT-263 in the following cell lines: HCT 116 cells, HS294T cells, Calu 1 cells, NCI-H460 cells, Calu-6 cells, and NCI-H727 cells.
  • Figures 7A and 7B depict representative volcano plots for two in vitro assays completed on a CALU-6 KRAS gl2V cell line using a combination of Compound 1 and ABT- 263. The height of the plot peaks suggest a synergistic effect is achieved at certain combination doses.
  • Figures 8 A and 8B depict representative volcano plots for two in vitro assays completed on an NCI-H727 cell line using a combination of Compound 1 and ABT-263.
  • the height of the plot peaks suggest a synergistic effect is achieved at certain combination doses.
  • Figures 9 A and 9B depict representative volcano plots for two in vitro assays completed on an HCT-116 colorectal cancer cell line using a combination of Compound 1 and ABT-263. The height of the plot peaks suggest an additive effect is achieved at certain combination doses.
  • Figures 10A and 10B depict representative volcano plots for two in vitro assays completed on a Mia Paca pancreatic cancer cell line using a combination of Compound 1 and ABT-263. The height of the plot peaks suggest an additive effect is achieved at certain combination doses.
  • Figures 11A and 11B depict representative volcano plots for two in vitro assays completed on an HS294T melanoma cell line using a combination of Compound 1 and ABT- 263.
  • the height of the plot peaks suggest an additive or possibly antagonistic effect is achieved at certain combination doses.
  • Figures 12A and 12B depict representative volcano plots for two in vitro assays completed on a Calu-1 lung cancer cell line using a combination of Compound 1 and ABT-263. The height of the plot peaks suggest an additive effect is achieved at certain combination doses.
  • Figures 13A and 13B depict representative volcano plots for two in vitro assays completed on an NCI-H460 cell line using a combination of Compound 1 and ABT-263. The height of the plot peaks suggest an additive effect is achieved at certain combination doses.
  • a Bcl-2 pathway modulator is an agent as described herein, infra.
  • a Bcl-2 pathway modulator is any Bcl-2 pathway modulator known to one of ordinary skill in the art. Such modulators are described herein, infra.
  • a disease or disorder associated with one or both of ERKl and ERK2 includes those in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role, including one or both of ERKl and ERK2 as well as other nodes in the MAPK pathway upstream from ERK (such as Ras, Raf and Mek).
  • another embodiment of the present invention relates to preventing, treating, stabilizing or lessening the severity or progression of one or more diseases in which one or both of ERKl and ERK2, or a mutant thereof, is known or suspected to play a role.
  • the present invention relates to a method of treating or lessening the severity of a proliferative disorder, wherein said method comprises administering to a patient in need thereof Compound 1 in combination with a Bcl-2 pathway modulator.
  • treat refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disease or disorder, or one or more symptoms of the disease or disorder.
  • treatment refers to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and/or relieving a disease or disorder, or one or more symptoms of the disease or disorder, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • the term “treating” includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • treating includes preventing relapse or recurrence of a disease or disorder.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered in combination with a Bcl-2 pathway modulator selected from TM1206, TW-3, N- (4-(4-((2-(4-chlorophenyl)-5 ,5-dimethyl- 1 -cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoyl)- 4-(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl-)propyl)amino)-3-
  • a Bcl-2 pathway modulator selected from TM1206, TW-3, N- (4-(4-((2-(4-chlorophenyl)-5 ,5-dimethyl- 1 -cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoyl)- 4-(((lR)-3-(morpholin-4-yl)-l-((
  • a Bcl-2 pathway modulator is BAM7.
  • an ERK inhibitor can treat disease or disorders in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role, including one or both of ERKl and ERK2 as well as other nodes in the MAPK pathway upstream from ERK (such as Ras, Raf and Mek).
  • ERK is a downstream target
  • ERK inhibitors are believed to be able to overcome, in some instances, drug resistance induced by inhibitors of targets upstream of ERK within the MAPK pathway.
  • RAF or MEK utilized in the treatment of K-RAS and B-RAF mutant tumors have resulted in such drug resistance.
  • drug resistance has been associated with other tumors driven by hyperactivation of the MAPK pathway (such as NF1 mutant tumors).
  • Kinase selectivity was achieved through silencing the selective Cys in a combination of the interactions between the covalent inhibitors of the invention and unique amino acids in the ATP binding pocket. Targeting the selective Cys provides for prolonged pharmacodynamics in silencing ERK activity, as well as potential lower doses in cancer treatment, compared to reversible inhibitors.
  • the activity of Compound 1, and pharmaceutically acceptable salts thereof, as an inhibitor of one or both of an ERKl and ERK2 kinase, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of downstream phosphorylation, changes in gene expression, subsequent functional markers and consequences, and/or kinase activity of one or both of activated ERKl and ERK2 kinase, or a mutant thereof. Alternate in vitro assays quantitate the ability of the test compound to bind to one or both of ERKl and ERK2.
  • Test compound binding may be measured by radiolabeling the test compound prior to binding, isolating one or both of the compound / ERKl complex and the compound / ERK2 complex, and determining the amount of radiolabel bound.
  • test compound binding may be determined by running a competition experiment where test compounds are incubated with one or both of ERKl and ERK2 kinase bound to known radioligands.
  • Test compound binding may be determined by competition with an ERK covalent probe that is amenable to further functionalization with a detection probe, such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification.
  • a detection probe such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification.
  • a detection probe such as, for example, a fluorophore, biotin conjugate, radiolabel, or any other probe that facilitates its quantification
  • Compound 1, and pharmaceutically acceptable salts thereof are inhibitors of one or both of ER 1 and ERK2 protein kinases, and ERK1 and ERK2 are downstream targets within the MAPK pathway.
  • ER 1 and ERK2 protein kinases are inhibitors of one or both of ER 1 and ERK2 protein kinases, and ERK1 and ERK2 are downstream targets within the MAPK pathway.
  • such compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder in which activation of the MAPK pathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play a role.
  • Such disease, condition, or disorder may be referred to herein as associated with the MAPK pathway or alternatively as associated with one or both of ERKl and ERK2.
  • Such diseases, conditions, or disorders may also be referred to herein as an "ERKl- or ERK2 -mediated disease, condition, or disorder.”
  • the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of the MAPK pathway (at any level in Ras-Raf-Mek-ERK), including one or both of ERKl and ERK2 protein kinases, is implicated in said disease, condition, or disorder wherein said method comprises administering to a patient in need thereof Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator.
  • the term “resistance” may refer to changes in a wild-type nucleic acid sequence coding a target protein, and/or to the amino acid sequence of the target protein and/or to the amino acid sequence of another protein, which changes, decreases or abolishes the inhibitory effect of the inhibitor on the target protein.
  • the term “resistance” may also refer to overexpression or silencing of a protein differing from a target protein that can reactivate the MAPK pathway or other survival pathways.
  • a Bcl-2 pathway modulator is selected from TM1206, TW-3, N-(4-(4-((2-(4-chlorophenyl)-5 ,5 -dimethyl- 1 -cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 - yl)benzoyl)-4-(((lR)-3-(morpholin-4-yl)-l-((phenylsulfanyl)methyl-)propyl)amino)-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide (ABT-263, Navitoclax), N-(4-(4-((4'-chloro(l,l'- biphenyl)-2-yl)methyl)piperazin- 1 -yl)benzoyl)-4-((( 1 R)-3 -(dimethylamino)- 1 - ((phenylsul)
  • a Bcl-2 pathway modulator is ABT-199 or ABT-263.
  • General diseases, conditions, or disorders treated by Compound 1, and pharmaceutically acceptable salts thereof, in combination with a Bcl-2 pathway modulator include cancer, an autoimmune disorder, a neurodegenerative or neurological disorder, liver disease, a cardiac disorder, schizophrenia, or a bone-related disorder.
  • the present invention provides a method for treating an ER 1- or ERK2 -mediated disease, condition, or disorder comprising administering to a patient in need thereof Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator.
  • the present invention relates to a method of treating or lessening the severity of a disease, condition, or disorder selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone -related diseases, wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator.
  • the cancer is a RAF inhibitor-resistant cancer.
  • the RAF inhibitor-resistant cancer is a BRAF inhibitor-resistant cancer.
  • the cancer is a MEK inhibitor-resistant cancer.
  • the cancer is a MAPK pathway-mediated cancer.
  • the cancer is a BRAF-mutated cancer.
  • the BRAF-mutated cancer is a BRAF V600 -mutated cancer, such as BRAF
  • the cancer is a RAS-mutated cancer.
  • the RAS-mutated involves codons 12, 13, or 61.
  • the RAS-mutated cancer is a KRAS-mutated cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the RAS-mutated cancer is an NRAS-mutated cancer, including, but not limited to, NRAS Q61R , NRAS Q61K , NRAS Q61L , or NRAS Q61H .
  • the RAS-mutated cancer is an HRAS-mutated cancer, including, but not limited to, HRAS G12V , HRAS Q61R , and HRAS G12S .
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is selected from multiple myeloma, breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach (gastric), skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung, bone, colon, thyroid, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma (including uveal melanoma) sarcoma, bladder carcinoma, liver carcinoma (e.g., hepatocellular
  • the cancer is relapsed. In some embodiments, the cancer is refractory. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is metastatic. [0071] In some embodiments, the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is selected from carcinoma, lymphoma, blastoma, sarcoma, and leukemia. In some embodiments, a sarcoma is a soft tissue sarcoma.
  • a lymphoma is non-Hodgkin's lymphoma. In some embodiments, a lymphoma is large cell immunoblastic lymphoma.
  • the cancer is selected from adenocarcinoma; adenoma; adrenocortical cancer; bladder cancer; bone cancer; brain cancer; breast cancer; cancer of the buccal cavity; cervical cancer; colon cancer; colorectal cancer; endometrial or uterine carcinoma; epidermoid carcinoma; esophageal cancer; eye cancer; follicular carcinoma; gallbladder cancer; prostate, AML, multiple myeloma (MM), gastrointestinal cancer, such as, for example, gastrointestinal stromal tumor; cancer of the genitourinary tract; glioblastoma; hairy cell carcinoma; various types of head and neck cancer; hepatic carcinoma; hepatocellular cancer; Hodgkin's disease; keratoacanthoma; kidney cancer; large cell carcinoma; cancer
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is selected from melanoma, colorectal cancer, lung cancer, or pancreatic.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is melanoma.
  • the melanoma is uveal melanoma.
  • the melanoma is a melanoma of the skin.
  • the melanoma is locally advanced.
  • the melanoma is metastatic.
  • the melanoma is recurring.
  • the melanoma is BRAF v600 -mutated melanoma. In certain embodiments, the melanoma is a RAS-mutated melanoma. In some embodiments, the melanoma is NRAS- mutated melanoma. In certain embodiments, the melanoma is wild type for KRAS, NRAS or BRAF. In certain embodiments, the melanoma is a BRAF inhibitor-resistant (e.g., Vemurfenib- resistant, dabrafenib-resistant, encorafenib -resistant, etc.) melanoma.
  • BRAF inhibitor-resistant e.g., Vemurfenib- resistant, dabrafenib-resistant, encorafenib -resistant, etc.
  • the cancer is a VemR (i.e., Vemurfenib-resistant) BRAF-mutated melanoma.
  • the melanoma is relapsed. In some embodiments, the melanoma is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is colorectal cancer.
  • the colorectal cancer is locally advanced.
  • the colorectal cancer is metastatic.
  • the colorectal cancer is a BRAF-mutated colorectal cancer.
  • the colorectal cancer is a BRAF v600 -mutated colorectal cancer.
  • the colorectal cancer is a RAS-mutated colorectal cancer.
  • the colorectal cancer is a KRAS-mutated colorectal cancer. In certain embodiments, the colorectal cancer is a NRAS-mutated colorectal cancer. In some embodiments, the colorectal cancer is relapsed. In some embodiments, the colorectal cancer is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is pancreatic cancer.
  • the pancreatic cancer is locally advanced.
  • the pancreatic cancer is metastatic.
  • the pancreatic cancer is a pancreatic ductal adenocarcinoma (PDAC).
  • the pancreatic cancer is a RAS-mutated pancreatic cancer.
  • the pancreatic cancer is a KRAS-mutated pancreatic cancer.
  • the pancreatic cancer is KRAS-mutated pancreatic cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D ,or KRAS Q61L/H/R .
  • the pancreatic cancer is relapsed.
  • the pancreatic cancer is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is a papillary thyroid cancer.
  • the papillary thyroid cancer is locally advanced.
  • the papillary thyroid cancer is metastatic.
  • the papillary thyroid cancer is recurring.
  • the papillary thyroid cancer is BRAF-mutated papillary thyroid cancer.
  • the papillary thyroid cancer is BRAF v600 -mutated papillary thyroid cancer.
  • the papillary thyroid cancer is relapsed.
  • the papillary thyroid cancer is refractory. In some embodiments, the papillary thyroid cancer may include undifferentiated or dedifferentiated histology.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is lung cancer.
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the lung cancer is locally advanced.
  • the lung cancer is metastatic.
  • the lung cancer is a RAS-mutated lung cancer.
  • the lung cancer is KRAS-mutated lung cancer.
  • the lung cancer is a KRAS- mutated lung cancer, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the lung cancer is relapsed.
  • the lung cancer is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is a leukemia.
  • a leukemia is a chronic leukemia.
  • a leukemia is chronic myeloid leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia (AML).
  • a leukemia is acute monocytic leukemia (AMoL, or AML-M5).
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is a CNS cancer, for instance CNS tumors.
  • a CNS tumor is a glioblastoma or glioblastoma multiforme (GBM).
  • GBM glioblastoma multiforme
  • the present invention relates to a method of treating stomach (gastric) and esophageal tumors and cancers.
  • the RAS-mutated multiple myeloma is a KRAS-mutated multiple myeloma, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the multiple myeloma is relapsed. In some embodiments, the multiple myeloma is refractory.
  • the present invention relates to a method of treating a cancer, wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • the HCC is locally advanced.
  • the HCC is metastatic.
  • the HCC is a RAS-mutated HCC.
  • the HCC is KRAS-mutated HCC.
  • the HCC is a KRAS- mutated HCC, including, but not limited to, KRAS G12C/D/V , KRAS G13C/D , or KRAS Q61L/H/R .
  • the hepatocellular carcinoma is relapsed. In some embodiments, the hepatocellular carcinoma is refractory.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
  • a Bcl-2 pathway modulator wherein the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is selected from breast, colorectal, lung, melanoma, pancreatic, or thyroid.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is selected from colorectal, lung, melanoma, or pancreatic.
  • the present invention relates to a method of treating a cancer wherein the method comprises administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator, wherein the cancer is selected from colorectal, melanoma, or pancreatic.
  • provided methods comprise administration to a patient in need thereof Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 pathway modulator.
  • a Bcl-2 pathway modulator As used herein, the term "in combination" with regard to administration of Compound 1 and a Bcl-2 pathway modulator means that each of Compound 1 and the Bcl-2 pathway modulator can be administered to the patient in any order (i.e., simultaneously or sequentially) or together in a single composition, formulation, or unit dosage form.
  • Compound 1, or a pharmaceutically acceptable salt thereof, and the Bcl-2 pathway modulator can be administered on the same day or on different days and in any order as according to an appropriate dosing protocol.
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2 comprising administering to a patient in need thereof a Bcl-2 pathway modulator in combination with a particular total daily dose of Compound 1, wherein the total daily dose of Compound 1 is selected from about about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg,
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2 comprising administering to a patient in need thereof a Bcl-2 pathway modulator in combination with a particular total daily dose of Compound 1, wherein the total daily dose of Compound 1 is selected from about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2 comprising administering to a patient in need thereof a Bcl-2 pathway modulator in combination with a particular total daily dose of Compound 1, wherein the total daily dose of Compound 1 is selected from about 10 mg to about 500 mg, or about 10 mg to about 450 mg, or about 10 mg to about 425 mg, or about 10 mg to about 400 mg, or about 10 mg to about 375 mg, or about 10 mg to about 350 mg, or about 10 mg to about 325 mg, or aboutlO mg to about 300 mg, or about 10 mg to about 275 mg, or about 10 to about 250 mg, or about 10 to about 225 mg, or about 10 mg to about 200 mg, or about 10 mg to about 190 mg, or about 10 mg to about 180 mg, or about 10 mg to about 170 mg, or about 10 mg to about 160 mg, or about 10 mg to about 150 mg,
  • the present invention provides a method of treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2 comprising administering to a patient in need thereof a Bcl-2 pathway modulator in combination with a particular total daily dose of Compound 1, wherein the total daily dose of Compound 1 is selected from about 100 mg to about 3000 mg, or about 500 mg to about 3000 mg, or about 100 mg to about 2500 mg, or about 500 mg to about 2500 mg, or about 100 mg to about 2200 mg, or about 500 mg to about 2200 mg, or about 600 mg to about 2200 mg, or about 700 mg to about 2200 mg, or about 800 to about 2200 mg, or about 800 to about 2100 mg, or about 800 to about 2000 mg. In certain embodiments, the daily dose is about 800 mg to about 2000 mg.
  • a total daily dose of Compound 1 is administered once daily (QD), wherein the dose is selected from about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 80 mg, about 120 mg, about 180 mg, about 330 mg, about 480 mg, or about 640 mg.
  • a total daily dose of Compound 1 is administered once daily (QD), wherein the dose is selected from about 20 mg, about 40 mg, about 80 mg, or about 160 mg.
  • the present invention provides methods for treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2, comprising administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a Bcl-2 pathway modulator, wherein said modulator is administered in an amount of about 0.1 mg/day to about 1200 mg/day, about 1 mg/day to about 100 mg/day, about 10 mg/day to about 1200 mg/day, about 10 mg/day to about 100 mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to about 1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day to about 800 mg/day or about 600 mg/day to about 800 mg/day.
  • methods disclosed herein comprise the administration of 0.1 mg/day, 0.5 mg/day, 1 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 45 mg/day, 50 mg/day, 60 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, 400 mg/day, 600 mg/day or 800 mg/day of a Bcl-2 pathway modulator to a patient in need thereof.
  • the present invention provides methods for treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2, comprising administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a Bcl-2 pathway modulator, wherein the total daily dose of the modulator is selected from about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about
  • Compound 1, or a pharmaceutically acceptable salt thereof is preferably formulated in unit dosage form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of Compound 1, or a pharmaceutically acceptable salt thereof, and compositions thereof, will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of Compound 1; the duration of the treatment; drugs used in combination or coincidental with Compound 1, and like factors well known in the medical arts.
  • the unit dosage forms described herein refer to an amount of Compound 1, i.e. the free base form of the active pharmaceutical ingredient, which may be provided as the free base or as a pharmaceutically acceptable salt thereof.
  • a unit dosage formulation of the present invention provides about 1 mg, 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • the present invention provides methods for treating, stabilizing or lessening the severity or progression of one or more diseases or disorders associated with one or both of ER 1 and ERK2, comprising administering to a patient in need thereof a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a Bcl-2 pathway modulator, wherein modulator is administered in unit dosage formulations that comprise between about 0.1 mg and about 2000 mg, about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg and about 1000 mg.
  • a Bcl-2 pathway modulator can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • Compound 1, or a pharmaceutically acceptable salt thereof, and/or a Bcl-2 pathway modulator may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents.
  • Dosage forms for topical or transdermal administration of Compound 1, or a pharmaceutically acceptable salt thereof, and/or a Bcl-2 pathway modulator include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • cells were plated at a density of 3000 cells/well in 90 of growth media on 96 well clear bottom black-well plates (Corning Cat# 3904) and incubated overnight under standard cell culture growth conditions at 37 °C 5% C0 2 .
  • the outer most rows and columns of wells were filled with culture media, without cells, to avoid evaporation effects on subsequent readouts.
  • the cells were treated with either 9 point 3 -fold dilutions of Compound 1 alone, or 9 point 3 -fold dilutions of ABT-199 or ABT-263 alone, or a combination of Compound 1 and either ABT-199 or ABT-263, or DMSO vehicle control.
  • the final concentrations in treatment wells for each compound was: (in nM) 10000.00, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0.
  • Each treatment was contained in 10 treatment media added to the respective wells. Each concentration was tested in triplicate.
  • Results are depicted graphically in Figures 1-4. A curve crossing below the X-axis indicates that cell number has dropped below the starting point (i.e., the cells are dying).
  • NCI-H460 cells were treated with a 9-point dose dilution of Compound 1 (A, trend line with circles) or ABT-263 (B, trend line with triangles), ABT-199 (B, trend line with circles) ranging from 1.52 nM to 10000.00 nM and DMSO vehicle control.
  • ABT-199 and ABT-263 induce cytostatic (growth-inhibitory) effect but not cell death, as noted by the dose-response curve remaining above the X-axis.
  • Compound 1 induces cell-death (cytotoxic) effect (noted by the curve crossing the X-axis) at 9705.10 nM.
  • Combination of Compound 1 and ABT-199 and Compound 1 and ABT-263 induce cell death effect at a lower dose (5956.62 nM and 3698.28 nM, respectively) than treatment with Compound 1 alone, and of larger magnitude (95.1 and 96.9 percent, respectively, compared to 4.2 percent induced by Compound 1 alone).
  • NCI-H727 cells were treated with a 9-point dose dilution of Compound 1 (A, trend line with circles), ABT-263 (B, trend line with triangles), or ABT-199 (B, trend line with circles) ranging from 1.52 nM to 10000.00 nM and DMSO vehicle control.
  • ABT-199 induces cytostatic (growth-inhibitory) effect but not cell death, as noted by the dose-response curve remaining above the X-axis.
  • Compound 1 induces cell- death (cytotoxic) effect (noted by the curve crossing the X-axis) at 762.08 nM.
  • ABT-263 induces cytotoxic effect at 10,000.00 nM concentration.
  • Combination of Compound 1 and ABT- 199 and Compound 1 and ABT-263 induce cell death effect at a lower dose (1051.96 nM and 542.00 nM, respectively) than treatment with Compound 1 alone, and of slightly larger magnitude (89.2 and 99.0 percent, respectively, compared to 87.3 percent induced by Compound 1 alone).
  • NCI-H522 cells were treated with a 9-point dose dilution of Compound 1 (A, trend line with circles), ABT-263 (B, trend line with triangles), or ABT-199 (B, trend line with circles) ranging from 1.52 nM to 10000.00 nM and DMSO vehicle control.
  • ABT-199 and ABT-263 induce cytostatic (growth-inhibitory) effect but not cell death, as noted by the dose-response curve remaining above the X-axis.
  • Compound 1 induces cell-death (cytotoxic) effect (noted by the curve crossing the X-axis) at 3006.08 nM.
  • Combination of either Compound 1 and ABT-199 or Compound 1 and ABT-263 induce cell death effect of larger magnitude (64.6 and 97.2 percent, respectively, compared to 28.9 percent induced by Compound 1 alone) and in case of ABT-263 at a lower dose than Compound 1 alone (2333.45 nM compared to 3006.08 nM for Compound 1 alone).
  • NCI-H1755 cells were treated with a 9-point dose dilution of Compound 1 (A, trend line with circles), ABT-263 (B, trend line with triangles), or ABT-199 (B, trend line with circles) ranging from 1.52 nM to 10000.00 nM and DMSO vehicle control.
  • Compound 1 induces cell-death (cytotoxic) effect (noted by the curve crossing the X-axis) at 644.17 nM.
  • ABT-199 and ABT-263 induce cell death at higher concentration of 10000.00 nM.
  • Combination of Compound 1 and ABT-199 and Compound 1 and ABT-263 induce cell death at the same concentration as Compound 1 single agent treatment. (630.95 nM and 534.56 nM, respectively, compared to 644.17 for compound 1 alone).
  • aABT-263 vehicle is 10% ethanol, 30% polyethylene glycol 400, and 60% Phosal 50 PG
  • the cells were treated with either 9 point 3-fold dilutions of Compound 1 alone, or 9 point 3-fold dilutions of ABT-263 alone, or a combination of Compound 1 and ABT-263, or DMSO vehicle control.
  • the final concentrations in treatment wells for each compound was: (in nM) 10000.00, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0.
  • Compound 1 was combined at each dilution level with a select constant dose of ABT-263. Each treatment was contained in 10 treatment media added to the respective wells. Each concentration was tested in triplicate.
  • Volcano Plots Representative volcano plots (i.e., plots used to graphically represent synergistic effects of a provided drug combination) are provided for assays completed as described above using Compound 1 and ABT-263 on various cell line.
  • the x-axis shows the 9 point dose titration of Compound 1 and DMSO control; the y- axis shows three individual fixed concentrations of ABT-263 in each experiment; and the z-axis shows the magnitude of the effect, with different patterns denoting different percent improvement over the additive effect of the specific compound combinations, as specified in each figure.
  • Figure 10 depicts representative volcano plots for two in vitro assays completed on a Mia Paca pancreatic cancer cell line using a combination of Compound 1 and ABT-263. The height of the plot peaks suggest an additive effect is achieved at certain combination doses.

Abstract

La présente invention concerne des méthodes de traitement, de stabilisation ou de réduction de la gravité ou de l'évolution d'une maladie ou d'un trouble associé à ERK1 et/ou ERK2.
PCT/US2015/044932 2014-08-13 2015-08-12 Combinaisons d'un inhibiteur de erk et d'un modulateur de la voie bcl-2 et méthodes associées WO2016025652A1 (fr)

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