WO2016025650A1 - Combinaisons d'un inhibiteur de erk et d'un inhibiteur cdk4/6 et méthodes associées - Google Patents

Combinaisons d'un inhibiteur de erk et d'un inhibiteur cdk4/6 et méthodes associées Download PDF

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WO2016025650A1
WO2016025650A1 PCT/US2015/044930 US2015044930W WO2016025650A1 WO 2016025650 A1 WO2016025650 A1 WO 2016025650A1 US 2015044930 W US2015044930 W US 2015044930W WO 2016025650 A1 WO2016025650 A1 WO 2016025650A1
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cancer
compound
inhibitor
cdk4
mutated
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PCT/US2015/044930
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Ida ARONCHIK
Gordon L. BRAY
Ellen H. Filvaroff
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Celgene Avilomics Research, Inc.
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    • 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
    • A61K31/495—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
    • 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

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 CDK4/6 (cyclin-dependent kinase 4 and/or cyclin-dependent kinase 6) inhibitor.
  • a CDK4/6 cyclin-dependent kinase 4 and/or cyclin-dependent kinase 6
  • the inhibitor of one or both of ERKl and ERK2 is Compound 1 ⁇ N-(2-((2-((2-methoxy-5-methylpyridin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)-5-methylphenyl)acrylamide):
  • Figure 1 depicts a graph showing tolerability of combination treatment with Compound 1 and PD-332991 in nine female nu/nu mice over five days.
  • Figure 2 depicts a graph showing the maximum effect (Emax) of Compound 1 with PD-0332991 on HCT 116 cells.
  • Figures 3A, 3B, 3C, 3D, 3E and 3F depict graphs showing the maximum effect (Emax) of Compound 1 with GDC0980 (Fig. 3A) or PD-0332991 (Figs. 3B, 3C, 3D. 3E and 3F) on Mia Paca cells (Fig. 3A), Calu 6 cells (Fig. 3B), HS294T cells (Fig. 3C), NCI-H460 cells (Fig. 3D), Calu 1 cells (Fig. 3E), and NCI-H727 cells (Fig. 3F).
  • Figures 4A and 4B depict representative volcano plots for two in vitro assays completed on an NCI-H460 cell line using a combination of Compound 1 and PD332991. The height of the plot peaks suggests a synergistic effect is achieved at certain combination doses.
  • Figures 5A and 5B 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 PD332991. The height of the plot peaks suggests an additive effect is achieved at certain combination doses.
  • Figure 6 depicts a representative volcano plot for an in vitro assay completed on a Mia Paca pancreatic cancer cell line using a combination of Compound 1 and PD332991. The height of the plot peaks suggests a synergistic effect is achieved at certain combination doses.
  • Figures 7 A and 7B depict representative volcano plots for two in vitro assays completed on an HS294T melanoma cancer cell line using a combination of Compound 1 and PD332991. The height of the plot peaks suggests an antagonistic effect is achieved at certain combination doses.
  • Figures 8 A and 8B 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 PD332991. The height of the plot peaks suggests an additive effect is achieved at certain combination doses.
  • Figures 9 A and 9B depict representative volcano plots for two in vitro assays completed on a Calu-6 lung cancer cell line using a combination of Compound 1 and PD332991. The height of the plot peaks suggests an additive effect is achieved at certain combination doses.
  • Figures 10A and 10B depict representative volcano plots for two in vitro assays completed on an NCI-H727 lung cancer cell line using a combination of Compound 1 and PD332991. The height of the plot peaks suggests an additive effect is achieved at certain combination doses.
  • 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 ERKl and ERK2 in combination with a CDK4/6 inhibitor.
  • an inhibitor of one or both of ERKl and ERK2 is Compound 1, or a pharmaceutically acceptable salt thereof, as described herein.
  • a CDK4/6 inhibitor is a compound as described herein, infra.
  • a CDK4/6 inhibitor is any CDK4/6 inhibitor known to one of ordinary skill in the art. Such CDK4/6 inhibitors are described herein, infra. Definitions
  • a "disease or disorder associated with one or both of ERK1 and ERK2” means any disease or other deleterious condition in which one or both of ERK1 and ERK2, or a mutant thereof, is known or suspected to play a role.
  • ERK1 and ERK2 are downstream targets within the MAPK pathway.
  • a disease or disorder associated with one or both of ER 1 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 CDK4/6 inhibitor.
  • the term "irreversible” or “irreversible inhibitor” refers to an inhibitor (i.e. a compound) that is able to be covalently bonded to a target protein kinase in a substantially non-reversible manner. That is, whereas a reversible inhibitor is able to bind to (but is generally unable to form a covalent bond to) the target protein kinase, and therefore can become dissociated from the target protein kinase, an irreversible inhibitor will remain substantially bound to the target protein kinase once covalent bond formation has occurred. Irreversible inhibitors usually display time dependency, whereby the degree of inhibition increases with the time with which the inhibitor is in contact with the enzyme.
  • Such methods include, but are not limited to, enzyme kinetic analysis of the inhibition profile of the compound with the protein kinase target, the use of mass spectrometry of the protein drug target modified in the presence of the inhibitor compound, discontinuous exposure, also known as "washout," experiments, and the use of labeling, such as radiolabeled inhibitor, to show covalent modification of the enzyme, as well as other methods known to one of skill in the art.
  • subject means a mammal and includes human and animal subjects, such as domestic animals (e.g., horses, dogs, cats, etc.).
  • a "therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response.
  • a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, condition, or disorder, to treat, diagnose, prevent, and/or delay the onset of the disease, condition, or disorder.
  • the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
  • the effective amount of compound in a formulation to treat a disease, condition, or disorder is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, condition, or disorder.
  • a "therapeutically effective amount" is at least a minimal amount of a compound, or composition containing a compound, which is sufficient for treating one or more symptoms of a disease or disorder associated with one or both of ER 1 and ERK2.
  • 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.
  • unit dosage form refers to a physically discrete unit of therapeutic formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
  • 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 ERK1 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 CDK4/6 inhibitor.
  • the inhibitor of one or both of ERKl and ERK2 is Compound 1 (N-(2- ((2-(( 2-methoxy-5-methylpyridin-4-yl)amino)-5- ( trifluoromethyl)pyrimidin-4- yl)amino)-5-methylphenyl)acrylamide):
  • Compound 1 is in the form of a phosphate salt.
  • 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 composition comprising Compound 1:
  • a dose or dosing regimen for a pharmaceutically acceptable salt of Compound 1 is selected from any of the doses or dosing regimens for Compound 1 as described herein.
  • Compound 1 is a potent inhibitor of the kinase activities of ERK1 and ERK2.
  • Compound 1 inhibits one or both of ERK1 and ERK2 with an IC 50 of about 10 to about 20 nM.
  • Compound 1 irreversibly inhibits ERK1 and ERK2 through formation of a covalent adduct with critical cysteine residues (amino acid 183 in ERK1 and 166 in ERK2) in the vicinity of the ATP binding pocket.
  • Compound 1 was shown to exhibit good overall kinase selectivity profile.
  • Compound 1 has demonstrated potent in vitro anti-pro liferative activity against a large number of cancer cell lines of various tissue origins. Bioinformatic analyses indicate that tumors with activating mutations of BRAF are particularly sensitive to Compound 1. Notably, of 27 BRAF -mutant cancer cell lines tested, 25 (93%) demonstrated sensitivity to Compound 1 inhibition (GI50 ⁇ 1 ⁇ ). In the same cancer cell panel screening, 28 of 37 (76%) KRAS-mutant cancer cell lines were sensitive to Compound 1. Compound 1 also exhibits inhibitory activity against, for instance, A375 melanoma cells that have acquired in vitro resistance to BRAF and MEK inhibition. This is of particular importance as resistance to BRAF inhibition has been commonly observed in human patients.
  • Such patients whose tumors demonstrated resistance to BRAF inhibitors are often cross-resistant to MEK inhibitors.
  • inhibitors of one or both of ERKl and ERK2, or a mutant thereof, such as Compound 1, or pharmaceutically acceptable salts thereof provide effective salvage therapy.
  • a CDK (Cyclin-dependent kinase) inhibitor is a chemical that inhibits the function of CDKs. It is used to treat cancers by preventing overproliferation of cancer cells. There are at least 10 CDK inhibitor compounds that have been in the clinic. Most of them are targeting multiple CDKs, but some are targeting specific CDKs, for example, CDK4 and/or CDK6.
  • CDK4/6 inhibitor refers to an inhibitor of CDK4, and/or an inhibitor of CDK6, and/or an inhibitor of both CDK4 and CDK6.
  • provided methods comprise combination therapies utilizing an inhibitor of one or both of ERKl and ERK2 and a CDK4/6 inhibitor.
  • 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 ERKl and ERK2, or a mutant thereof, comprising administering to a patient in need thereof Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor.
  • a CDK4/6 inhibitor is selected from PD-0332991, Flavopiridol, AT7519M, P276-00, SCH 727965, AG-024322, LEE011, LY2835219, P1446A- 05, BAY 1000394, SNS-032, pyrido[2,3-d]pyrimidines (e.g., pyrido[2,3-d]pyrimidin-7-ones and 2-amino-6-cyano-pyrido[2,3-d]pyrimidin-4-ones), triaminopyrimidines, aryl[a]pyrrolo[3,4- d]carbazoles, nitrogen-containing heteroaryl-substituted ureas, 5-pyrimidinyl-2-aminothiazoles, benzothiadiazines, acridinethiones, and isoquinolones.
  • pyrido[2,3-d]pyrimidines e.g., pyri
  • the pyrido[2,3-d]pyrimidine is a pyrido[2,3-d]pyrimidinone.
  • the pyrido[2,3-d]pyrimidinone is pyrido[2,3-d]pyrimidin-7-one.
  • the pyrido[2,3-d]pyrimidin-7-one is substituted by an aminoaryl or aminoheteroaryl group.
  • the pyrido[2,3-d]pyrimidin-7-one is substituted by an aminopyridine group.
  • the pyrido[2,3-d]pyrimidin-7-one is a 2-(2- pyridinyl)amino pyrido[2,3-d]pyrimidin-7-one.
  • the pyrido[2,3- d]pyrimidine compound is 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-l-yl-pyridin-2- ylamino)-8H- -pyrido-[2,3-d]pyrimidin-7-one (i.e., PD 0332991) or a pharmaceutically acceptable salt thereof.
  • the pyrido[2,3-d]pyrimidinone is a 2-amino-6-cyano- pyrido [2 , 3 -d]pyrimidin-4-one .
  • a CDK4/6 inhibitor is an aryl[a]pyrrolo[3,4-d]carbazole including, but not limited to naphthyl[a]pyrrolo[3,4-c]carbazoles, indolo[a]pyrrolo[3,4- c]carbazoles, quinolinyl[a]pyrrolo[3,4-c]carbazoles, and isoquinolinyl[a]pyrrolo[3,4- c]carbazoles.
  • a CDK4/6 inhibitor is a urea such as those compounds of Formula (I) described in U.S. Patent Publication No. 2007/0027147.
  • the urea is:
  • the 5-pyrimidinyl-2-aminothiazole has the structure:
  • the CDK4/6 inhibitor is a benzothiadiazine or acridinethiones compound, e.g., those, for example, disclosed in U.S. Patent Publication No. 2004/0006074, herein incorporated by reference in their entirety.
  • the benzothiadiazine is selected from the group consisting of 4-(4-fluorobenzylamino)-l,2,3-benzothiadiazine-l,l- dioxide, 3-chloro-4-methyl-4H-benzo[e][l,2,4]thiadiazine-l,l-dioxide, and 3-chloro-4-ethyl-4H- benzo[e][l,2,4]thiadiazine-l,l-dioxide.
  • the acridinethione is selected from the group consisting of 3-amino-10H-acridone-9-thione (3ATA), 9(10H)-acridinethione, l,4-dimethoxy-10H-acridine-9-thione, and 2,2'-diphenyldiamine-bis-[N,N'-[3-amido-N- methylamino)- 10H-acridine-9-thione] ] .
  • 3-amino-10H-acridone-9-thione (3ATA)
  • 9(10H)-acridinethione 9(10H)-acridinethione
  • l,4-dimethoxy-10H-acridine-9-thione l,4-dimethoxy-10H-acridine-9-thione
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered in combination with a CDK4/6 inhibitor selected from LEE011, palbociclib (PD- 0332991), and Abemaciclib (LY2835219).
  • a CDK4/6 inhibitor selected from LEE011, palbociclib (PD- 0332991), and Abemaciclib (LY2835219).
  • a CDK4/6 inhibitor is a compound disclosed in the patent publications listed below in Table A:
  • Table A US Patent Publication No. 20140031325; US Patent Publication No. 20140080838; US Patent Publication No. 20130303543; US Patent Publication No. 2007/0027147; US Patent Publication No. 2003/0229026; US Patent Publication No 2004/0048915; US Patent Publication No. 2004/0006074; US Patent Publication No. 2007/0179118; each of which is incorporated by reference herein in its entirety.
  • Compound 1, and pharmaceutically acceptable salts thereof described herein is an inhibitor of one or both of ERKl and ERK2.
  • ERK is one of the key components in the RAS-RAF-MEK-ERK MAPK pathway and that ERK1 and ERK2 are downstream nodes within the MAPK pathway.
  • 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
  • the term "measurably inhibit”, as used herein means a measurable change in one or both of ERKl and ERK2 protein kinase activity between a sample comprising a provided composition, and one or both of an ERKl and ERK2 protein kinase and an equivalent sample comprising one or both of ERKl and ERK2 protein kinase in the absence of a provided composition.
  • Such measurements of protein kinase activity are known to one of ordinary skill in the art and include those methods set forth herein below and/or in the Examples of the '230 publication.
  • Compound 1, and pharmaceutically acceptable salts thereof are inhibitors of one or both of ERKl and ERK2 protein kinases, and ERKl and ERK2 are downstream targets within the MAPK pathway.
  • ERKl 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 CDK4/6 inhibitor.
  • the present invention relates to a method of inhibiting one or both of ERKl and ERK2 protein kinase activity in a patient comprising the step of administering to said patient a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor, or a composition comprising any of the foregoing.
  • the present invention provides a method for treating a disease, condition, or disorder mediated by one or both of ERK1 and ERK2 kinase, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient Compound 1, or pharmaceutically acceptable salts thereof, in combination with a CDK4/6 inhibitor, or a pharmaceutically acceptable composition comprising any of the foregoing.
  • a disease, condition, or disorder mediated by one or both of ERK1 and ERK2 kinase, or a mutant thereof in a patient in need thereof, comprising the step of administering to said patient Compound 1, or pharmaceutically acceptable salts thereof, in combination with a CDK4/6 inhibitor, or a pharmaceutically acceptable composition comprising any of the foregoing.
  • the present invention provides a method for overcoming drug resistance to Raf or MEK inhibitors, comprising the step of administering to a patient an inhibitor compound of one or both of ERKl and ERK2, such as Compound 1, or a pharmaceutically acceptable salt thereof, either alone or in combination with a CDK4/6 inhibitor.
  • the mechanism of drug resistance is through mutation of a target protein or reactivation of the MAPK pathway.
  • 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.
  • treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is 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 is also continued after symptoms have resolved, for example to prevent, delay or lessen the severity of their recurrence.
  • the present invention provides a system for treating, stabilizing or lessening the severity of one or more diseases or disorders associated with one or more of ERKl and ERK2, the system comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor.
  • the present invention contemplates a system comprising any of the above-described CDK4/6 inhibitors.
  • a CDK4/6 inhibitor is selected from LEE011, palbociclib (PD- 0332991), Abemaciclib (LY2835219).
  • General diseases, conditions, or disorders treated by Compound 1, and pharmaceutically acceptable salts thereof, in combination with a CDK4/6 inhibitor 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 CDK4/6 inhibitor.
  • 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 CDK4/6 inhibitor.
  • 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 CDK4/6 inhibitor.
  • the cancer is recurring.
  • the cancer is refractory.
  • the cancer is metastatic.
  • the cancer is locally advanced.
  • 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 , KRAS , or
  • 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 CDK4/6 inhibitor, 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 carcinoma (
  • 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 CDK4/6 inhibitor, wherein the cancer is selected from carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • a sarcoma is a soft tissue sarcoma.
  • a lymphoma is non-Hodgkin's lymphoma.
  • 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 of the large intestine; laryngeal cancer; liver cancer; lung cancer, such as, for example, adenocarcinoma of the lung, anaplastic carcinoma of the lung, pa
  • 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 CDK4/6 inhibitor, wherein the cancer is selected from melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer (e.g., non-small cell lung cancer), breast cancer, endometrial cancer, prostate cancer, ovarian cancer, hepatocellular carcinoma (HCC), multiple myeloma (MM), and leukemia.
  • a leukemia is an acute leukemia.
  • a leukemia is acute myeloid leukemia.
  • a leukemia is acute lymphoblastic leukemia.
  • 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 CDK4/6 inhibitor, 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 CDK4/6 inhibitor, 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 CDK4/6 inhibitor, 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 CDK4/6 inhibitor, 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 CDK4/6 inhibitor, 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.
  • 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 CDK4/6 inhibitor, 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 CDK4/6 inhibitor, 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).
  • a leukemia is acute lymphoblastic leukemia (ALL). In certain embodiments, a leukemia is acute T cell leukemia. In certain embodiments, a leukemia is myelomonoblastic leukemia. In certain embodiments, a leukemia is human B cell precursor leukemia. In certain embodiments, a leukemia has a Flt3 mutation or rearrangement. In some embodiments, the leukemia is relapsed. In some embodiments, the leukemia is refractory.
  • ALL acute lymphoblastic leukemia
  • a leukemia is acute T cell leukemia.
  • a leukemia is myelomonoblastic leukemia.
  • a leukemia is human B cell precursor leukemia.
  • a leukemia has a Flt3 mutation or rearrangement. In some embodiments, the leukemia is relapsed. In some embodiments, the leukemia 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 CDK4/6 inhibitor, 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 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 CDK4/6 inhibitor, wherein the cancer is multiple myeloma (MM).
  • the multiple myeloma is locally advanced.
  • the multiple myeloma is metastatic.
  • the multiple myeloma is a RAS-mutated multiple myeloma.
  • the multiple myeloma is KRAS-mutated multiple myeloma.
  • 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 CDK4/6 inhibitor, 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 CDK4/6 inhibitor, wherein the cancer is selected from breast, colorectal, endometrial, hematological, leukemia (e.g., AML), liver, lung, melanoma, ovarian, pancreatic, prostate, or thyroid.
  • a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor
  • 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 CDK4/6 inhibitor, wherein the cancer is selected from breast, colorectal, endometrial, liver, lung, melanoma, ovarian, 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 CDK4/6 inhibitor, 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 CDK4/6 inhibitor, 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 CDK4/6 inhibitor, 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 CDK4/6 inhibitor.
  • the term "in combination" with regard to administration of Compound 1 and a CDK4/6 inhibitor means that each of Compound 1 and the CDK4/6 inhibitor 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 CDK4/6 inhibitor 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 ER 2 comprising administering to a patient in need thereof a CDK4/6 inhibitor in combination with a particular total daily dose of Compound 1, wherein the total daily dose of Compound 1 is selected from 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, about 190 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 ER 2 comprising administering to a patient in need thereof a CDK4/6 inhibitor 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 Attorney Docket No.
  • 2007878-0568 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, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, or about 3000 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 ER 2 comprising administering to a patient in need thereof a CDK4/6 inhibitor 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, or about 10
  • 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 ER 2 comprising administering to a patient in need thereof a CDK4/6 inhibitor 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 CDK4/6 inhibitor, wherein the CDK4/6 inhibitor 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 CDK4/6 inhibitor 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 CDK4/6 inhibitor, wherein the total daily dose of a CDK4/6 inhibitor 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 1 10 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
  • 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.
  • 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 CDK4/6 inhibitor, wherein Compound 1 is administered in unit dosage formulations that comprise between about 5 mg to about 1000 mg of Compound 1.
  • 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 1 15 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
  • 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 CDK4/6 inhibitor, wherein Compound 1 is administered in unit dosage formulations that comprise about 5 mg, 30 mg, or 150 mg of Compound 1.
  • a capsule formulation of the present invention provides about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of Compound 1.
  • 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.
  • Unit Dosage Forms of a CDK4/6 Inhibitor 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 CDK4/6 inhibitor, wherein the CDK4/6 inhibitor 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 of a CDK4/6 inhibitor.
  • unit dosage formulations comprising about 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 45 mg, 50 mg, 60 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 600 mg or 800 mg of a CDK4/6 inhibitor.
  • unit dosage formulations that comprise 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a CDK4/6 inhibitor.
  • unit dosage formulations that comprise about 5 mg, about 15 mg, about 20 mg, about 30 mg, about 45 mg, and about 50 mg of a CDK4/6 inhibitor.
  • Compound 1, or a pharmaceutically acceptable salt thereof, and compositions thereof according to methods of the present invention are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided above.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • provided methods comprise administering a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, one, two, three, or four times a day.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered once daily ("QD").
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.
  • twice daily administration refers to a compound or composition that is administered "BID", or two equivalent doses administered at two different times in one day.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered three times a day.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered "TID", or three equivalent doses administered at three different times in one day.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, is administered four times a day.
  • a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is administered "QID", or four equivalent doses administered at four different times in one day.
  • Compound 1 is administered to a patient under fasted conditions and the total daily dose is any of those contemplated above and herein.
  • Compound 1 is administered to a patient under fed conditions and the total daily dose is any of those contemplated above and herein.
  • Compound 1 is administered orally.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated.
  • provided methods comprise administering a pharmaceutically acceptable composition comprising a CDK4/6 inhibitor one, two, three, or four times a day.
  • a pharmaceutically acceptable composition comprising a CDK4/6 inhibitor is administered once daily ("QD").
  • a pharmaceutically acceptable composition comprising a CDK4/6 inhibitor is administered twice daily.
  • twice daily administration refers to a compound or composition that is administered "BID", or two equivalent doses administered at two different times in one day.
  • a pharmaceutically acceptable composition comprising a CDK4/6 inhibitor is administered three times a day.
  • a pharmaceutically acceptable composition comprising a CDK4/6 inhibitor is administered "TID", or three equivalent doses administered at three different times in one day.
  • a pharmaceutically acceptable composition comprising a CDK4/6 inhibitor is administered four times a day.
  • a pharmaceutically acceptable composition comprising a CDK4/6 inhibitor is administered "QID", or four equivalent doses administered at four different times in one day.
  • a CDK4/6 inhibitor is administered to a patient under fasted conditions and the total daily dose is any of those contemplated above and herein.
  • a CDK4/6 inhibitor is administered to a patient under fed conditions and the total daily dose is any of those contemplated above and herein.
  • a CDK4/6 inhibitor is administered orally for reasons of convenience.
  • a CDK4/6 inhibitor when administered orally, is administered with a meal and water.
  • the CDK4/6 inhibitor is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.
  • a CDK4/6 inhibitor when administered orally, is administered in a fasted state.
  • a CDK4/6 inhibitor 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.
  • compositions of Compound 1 and/or a CDK4/6 inhibitor are provided.
  • the present invention provides a pharmaceutically acceptable composition comprising Compound 1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutically acceptable composition of a CDK4/6 inhibitor.
  • a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof is separate from a composition comprising a CDK4/6 inhibitor.
  • Compound 1, or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor are present in the same composition.
  • 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.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • delayed absorption of parenterally administered Compound 1, or a pharmaceutically acceptable salt thereof, and/or a CDK4/6 inhibitor is accomplished by dissolving or suspending the compound in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of Compound 1, or a pharmaceutically acceptable salt thereof, and/or a CDK4/6 inhibitor, in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • 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
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Compound 1, or a pharmaceutically acceptable salt thereof, and/or a CDK4/6 inhibitor can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • Compound 1, or a pharmaceutically acceptable salt thereof, and/or a CDK4/6 inhibitor may be admixed with at least one 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.
  • 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. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of Compound 1, or a pharmaceutically acceptable salt thereof, and/or a CDK4/6 inhibitor 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.
  • the invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with Compound 1, or a pharmaceutically acceptable salt thereof, and/or a CDK4/6 inhibitor, or a composition comprising said compound.
  • the invention relates to a method of inhibiting one or both of ER 1 and ERK2 kinase, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor, or a composition comprising any of the foregoing.
  • the invention relates to a method of irreversibly inhibiting one or both of ERK1 and ERK2 kinase, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor, or a composition comprising any of the foregoing.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of one or both of ER 1 and ERK2, or a mutant thereof, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ- transplantation, biological specimen storage, and biological assays.
  • Another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor, or a composition comprising any of the foregoing.
  • the invention relates to a method of irreversibly inhibiting one or both of ERKl and ERK2 kinase, or a mutant thereof, activity in a patient comprising the step of administering to said patient Compound 1, or a pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor, or a composition comprising any of the foregoing.
  • the activity is inhibited irreversibly by covalently modifying Cys 183 of ERKl . In certain embodiments, the activity is inhibited irreversibly by covalently modifying Cys 166 of ERK2. In certain embodiments, the activity is inhibited irreversibly by covalently modifying Cys 183 of ERKl and Cys 166 of ERK2.
  • Compound 1 is prepared according to the following general procedure.
  • Step 2 can be carried out by adding Intermediate 1 to a suitable coupling partner in the presence of Na 2 C0 3 , a degassed solvent (e.g., tert-amyl alcohol), a suitable palladium catalyst (e.g., tris-dibenzylamino dipalladium) and a suitable phosphine ligand (e.g., Dave Phos) under conditions suitable to effect coupling.
  • a degassed solvent e.g., tert-amyl alcohol
  • a suitable palladium catalyst e.g., tris-dibenzylamino dipalladium
  • a suitable phosphine ligand e.g., Dave Phos
  • This experiment demonstrates the finding that female nu/nu mice tolerate combination treatment using the phosphate salt of Compound 1 and a CDK4/6 inhibitor (i.e., PD-332991) with no change in body weight.
  • PD-332991 and the phosphate salt of Compound 1 were formulated in 5% Captisol/0.2% Tween and dosed together in groups administered combinations.
  • aA correction factor of 1.21 was used to weigh the appropriate amount of Compound 1 salt to obtain the indicated free base equivalent doses.
  • a correction factor for PD-332991 was applied to correct for HCL salt to parent.
  • Plasma samples were collected post five doses from each single agent or combination group. At 4 hour PK sacrifice time, 2-3 animals per group were collected into 10% NBF and gross observations noted. As depicted in Figure 1 , treatment was well tolerated in all groups for 5 days, with 3-10% weight increase observed and minor clinical observations noted. At 60 mg/kg PD-332991 only, no clinical observations were noted. At 120 mg/kg PD-332991 only, one out of nine mice was pale on day 5. In the combination groups, no clinical observations were noted. Example 3
  • Emax is the effect a compound has on cell growth at a given concentration. It is evaluated both relative to control treatment and relative to cell number at time zero, and usually ranges from 100% to -100%.
  • an Emax of 100% indicates that the treated cells have grown as fast as the control cells; an Emax of 20% indicates that the treated cells have grown slower and their growth rate was 20% of the growth rate of cells in control treated wells; an Emax of -20% indicates that the cells have declined in number compared to the number of cells seeded at day zero (i.e., by 20%); an Emax of -100% indicates that the cells have declined in number compared to the number of cells seeded at day zero (i.e., by 100%, that is, all cells are dead). Values of >100%> indicate that the cells in the treated well have grown faster than the cells in the control well, typically indicating no negative effect (as opposed to a positive effect).
  • the present example demonstrates that in certain cell lines combination treatment with Compound 1 (free base) and a CDK4/6 inhibitor (e.g., PD0332991) yields certain synergistic results.
  • the cells were plated at density 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 final concentrations of Compound 1 in treatment wells were: (in nM) 10000.00, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, and 0.
  • Compound 1 was combined at each dilution level with a selected constant dose of PD0332991.
  • 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 two assays completed as described above using Compound 1 and PD332991 on NCI-H460 lung cancer cell lines.
  • the x-axis shows the 9 point dose titration of Compound 1 and DMSO control; the y-axis shows three individual fixed concentrations of PD332991 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.
  • synergy is defined as achieving a greater than additive effect with a particular drug combination.
  • An additive effect is a predicted additive effect, assuming independent action of each individual drug (i.e., Bliss independence). If a particular combination of drugs affords results which exceed the predicted additive effect, that combination is considered to be synergistic. If a particular combination of drugs affords results which fall short of the predicted additive effect, that combination is considered to be antagonistic.
  • the additive effect is determined by assuming that the first drug will inhibit 50% of the substrate population and the second drug will inhibit 50% of the remaining substrate population, leading to a predicted additive effect of 75% inhibition.
  • inhibition of greater than 75% of a substrate population with combination treatment using the two drugs suggests synergy.
  • inhibition of less than 75% of a substrate population with combination treatment using the two drugs suggests antagonism.
  • Figures 4-10 depict representative volcano plots for combination treatment of Compound 1 and PD332991 on various cell lines.
  • Figure 4 depicts representative volcano plots for two in vitro assays completed on an NCI-H460 cell line using a combination of Compound 1 and PD332991. The height of the plot peaks suggests a synergistic effect is achieved at certain combination doses.
  • Figure 5 depicts representative volcano plots for two in vitro assays completed on an HCT-116 colorectal cancer cell line using a combination of Compound 1 and PD332991. The height of the plot peaks suggests an additive effect is achieved at certain combination doses.
  • Figure 6 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 PD332991. The height of the plot peaks suggests a synergistic effect is achieved at certain combination doses.
  • Figure 7 depicts representative volcano plots for two in vitro assays completed on an HS294T melanoma cancer cell line using a combination of Compound 1 and PD332991. The height of the plot peaks suggests an antagonistic effect is achieved at certain combination doses.
  • Figure 8 depicts representative volcano plots for two in vitro assays completed on a
  • Calu-1 lung cancer cell line using a combination of Compound 1 and PD332991 The height of the plot peaks suggests an additive effect is achieved at certain combination doses.
  • Figure 9 depicts representative volcano plots for two in vitro assays completed on a
  • Calu-6 lung cancer cell line using a combination of Compound 1 and PD332991 The height of the plot peaks suggests an additive effect is achieved at certain combination doses.
  • Figure 10 depicts representative volcano plots for two in vitro assays completed on an
  • NCI-H727 lung cancer cell line using a combination of Compound 1 and PD332991 The height of the plot peaks suggests an additive effect is achieved at certain combination doses.

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Abstract

L'invention concerne des méthodes de traitement, de stabilisation ou d'atténuation de la sévérité ou de la progression d'une maladie ou d'un trouble associé à ERK1 et/ou ERK2.
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CN109803684B (zh) * 2016-08-23 2022-08-23 卫材 R&D 管理有限公司 用于治疗肝细胞癌的组合疗法
WO2018039324A1 (fr) 2016-08-23 2018-03-01 Eisai R&D Management Co., Ltd. Polythérapies pour le traitement du carcinome hépatocellulaire
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
EP4218820A2 (fr) 2017-03-16 2023-08-02 Eisai R&D Management Co., Ltd. Polythérapies pour le traitement du cancer du sein
WO2018170447A1 (fr) 2017-03-16 2018-09-20 Eisai R&D Management Co., Ltd. Polythérapies pour le traitement du cancer du sein
US11083722B2 (en) 2017-03-16 2021-08-10 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of breast cancer
US11913075B2 (en) 2017-04-01 2024-02-27 The Broad Institute, Inc. Methods and compositions for detecting and modulating an immunotherapy resistance gene signature in cancer
CN116036278A (zh) * 2017-05-16 2023-05-02 生物医学谷探索股份有限公司 用于治疗具有非典型braf突变的癌症的组合物和方法
US10689377B2 (en) 2017-11-15 2020-06-23 Mirati Therapeutics, Inc. KRas G12C inhibitors
US10647715B2 (en) 2017-11-15 2020-05-12 Mirati Therapeutics, Inc. KRas G12C inhibitors
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US20210030758A1 (en) * 2018-04-09 2021-02-04 G1 Therapeutics, Inc. Treatment of cancers having driving oncogenic mutations
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2020186101A1 (fr) 2019-03-12 2020-09-17 The Broad Institute, Inc. Procédés de détection, compositions et méthodes de modulation des cellules de sarcome synovial
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
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WO2022271939A1 (fr) * 2021-06-24 2022-12-29 Erasca, Inc. Polythérapie reposant sur des inhibiteurs d'erk1/2 et de cdk4/6

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