Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • 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
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/22—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2827—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

• the present invention relates to a medicament for treating or preventing cancer.
• Cancer is a disease in which cells proliferate uncontrollably due to genetic abnormalities.
• Chemotherapy is a medical treatment for cancer, and various anticancer drugs are used.
• many molecular targeting agents have been developed as anticancer drugs that act specifically on molecules specifically expressed in certain cancer cells or molecules whose expression is increased in cancer cells.
• molecular targeting agents include antibody drugs such as cetuximab, bevacizumab, and panitumumab (Patent Document 1), low-molecular drugs such as gefitinib, erlotinib, and afatinib (Patent Document 2), and arylamide derivatives having antitumor activity (Patent Document 1). 3) etc. are known.
• an object of the present invention is to provide a medicament that exhibits excellent effects in treating or preventing cancer.
• the present invention includes the following [1] to [130].
• a medicament for treating or preventing cancer which contains a compound represented by the following formula 1 (also referred to as "compound 1"), a salt thereof, or a solvate thereof, and is used in combination with a molecular targeting agent.
• a medicament for treating or preventing cancer which contains a molecular targeting agent and is used in combination with Compound 1 or a salt thereof or a solvate thereof.
• a method for treating or preventing cancer which comprises administering Compound 1 or a salt thereof or a solvate thereof and a molecular targeting agent to a subject.
• a molecular targeting agent for use in the treatment or prevention of cancer which is used in combination with Compound 1, a salt thereof, or a solvate thereof.
• [8] Use of a molecular targeting agent for the production of a medicament for treating or preventing cancer, which is used in combination with Compound 1, a salt thereof, or a solvate thereof.
• Molecular targeting agent or use for [15] The medicament, method, and use according to [14], wherein the KRAS-G12C selective inhibitor is at least one selected from the group consisting of sotorasib, adaglasib, salts thereof, and solvates thereof. Compound 1 or a salt thereof or a solvate thereof, a molecular targeting agent for use, or a use thereof. [16] Compound 1 or a salt thereof for the medicament, method, or use according to [14] or [15], wherein the KRAS-G12C selective inhibitor is adagrasib, a salt thereof, or a solvate thereof; Solvates, molecular targeting agents for use, or uses thereof.
• [17] Compound 1 or a salt thereof for the medicament, method, or use according to [14] or [15], wherein the KRAS-G12C selective inhibitor is sotorasib or a salt thereof or a solvate thereof; Solvates, molecular targeting agents for use, or uses thereof.
• the KRAS-G12C selective inhibitor is sotorasib, Compound 1 or a salt thereof for use in the medicament, method, or use according to any one of [14], [15], and [17] solvates, molecular targeting agents for use, or uses.
• the SHP2 inhibitor is at least one selected from the group consisting of RMC-4550, TNO155, SHP099, NSC-87877, RMC-4630, GDC-1971, salts thereof, and solvates thereof, Compound 1 or a salt thereof or a solvate thereof, a molecular targeting agent for use, or use for the medicament, method, or use according to any one of [12] to [18].
• the SHP2 inhibitor is at least one selected from the group consisting of RMC-4550, TNO155, GDC-1971, salts thereof, and solvates thereof.
• Compound 1 or a salt thereof or a solvate thereof a molecular targeting agent for use, or use for use in a medicament, method, or use as described in .
• Compound 1 or a salt thereof for use in the medicament, method, or use according to any one of [12] to [20] wherein the SHP2 inhibitor is RMC-4550, a salt thereof, or a solvate thereof. or solvates, molecular targeting agents for use, or uses thereof.
• Compound 1 or a salt thereof for use in the medicament, method, or use according to any one of [12] to [20] wherein the SHP2 inhibitor is TNO155 or a salt thereof, or a solvate thereof.
• [29] Compound 1 or a salt thereof for the medicament, method, or use according to [27] or [28], wherein the KRAS-G12C selective inhibitor is adagrasib or a salt thereof or a solvate thereof; Solvates, molecular targeting agents for use, or uses thereof.
• [31] Compound 1 or a salt thereof for the medicament, method, or use according to any one of [27], [28], and [30], wherein the KRAS-G12C selective inhibitor is sotorasib. solvates, molecular targeting agents for use, or uses.
• the SHP2 inhibitor is at least one selected from the group consisting of RMC-4550, TNO155, SHP099, NSC-87877, RMC-4630, GDC-1971, salts thereof, and solvates thereof, Compound 1 or a salt thereof or a solvate thereof, a molecular targeting agent for use, or use for the medicament, method, or use according to [32].
• the SHP2 inhibitor according to [32] or [33] is at least one selected from the group consisting of RMC-4550, TNO155, GDC-1971, salts thereof, and solvates thereof. Compound 1 or a salt thereof or a solvate thereof for use in a medicament, method, use, molecular targeting agent for use, or use.
• [35] Compound 1 or a salt thereof for use in the medicament, method, or use according to any one of [32] to [34], wherein the SHP2 inhibitor is RMC-4550, a salt thereof, or a solvate thereof. or solvates, molecular targeting agents for use, or uses thereof.
• the VEGF inhibitor is bevacizumab.
• the PD-1 system binding antagonist is an anti-PD-L1 antibody Compound 1 or a salt thereof or a solvate thereof, a molecule for use in the medicament, method, or use according to [40] Targeting agent or use.
• the above compound 1 or a salt thereof or a solvate thereof is the sodium salt of the above compound 1, and the above molecular targeting agent is a KRAS-G12C selective inhibitor, [1] to [14] and Compound 1 or a salt thereof or a solvate thereof for use, a molecular targeting agent for use, or use as described in any one of [19] to [27].
• Compound 1 or a salt thereof or a solvate thereof for the medicament, method, or use according to [44], wherein the KRAS-G12C selective inhibitor is sotorasib or a salt thereof or a solvate thereof A substance, a molecular targeting agent for use, or a use.
• the above compound 1 or a salt thereof or a solvate thereof is a sodium salt of the above compound 1, and the above molecular targeting agent is RMC-4550 or a salt thereof or a solvate thereof, [1] Compound 1 or a salt thereof or a solvate thereof for use in the medicament, method, or use according to any one of [21], [24], [25], and [32] to [35] molecular targeting agent or use.
• the above compound 1 or a salt thereof or a solvate thereof is the sodium salt of the above compound 1, and the above molecular targeting agent is TNO155 or a salt thereof or a solvate thereof, [1] to [ Compound 1 or a salt thereof or a solvent thereof for the medicament, method, or use according to any one of [20], [22], [24], [25], [32] to [34], and [36] compound, molecular targeting agent for use, or use.
• the above compound 1 or a salt thereof or a solvate thereof is the sodium salt of the above compound 1, and the above molecular targeting agent is GDC-1971 or a salt thereof or a solvate thereof, [1] ⁇ [20], [23] ⁇ [25], [32] ⁇ [34], and Compound 1 or a salt thereof or a solvate thereof for the medicament, method, or use according to any one of [37] , a molecular targeting agent for use, or a use.
• the above compound 1 or a salt thereof or a solvate thereof is the sodium salt of the above compound 1, and the above molecular targeting agent is bevacizumab, [1] to [25], [38], and [ Compound 1 or a salt thereof or a solvate thereof, a molecular targeting agent for use, or use for the medicament, method, or use according to any one of [39].
• the above compound 1 or a salt thereof or a solvate thereof is the sodium salt of the above compound 1, and the above molecular targeting agent is an anti-PD-L1 antibody, [1] to [25], [40] ], Compound 1 or a salt thereof or a solvate thereof, a molecular targeting agent for use, or use for the medicament, method, use, or use according to any one of [41].
• Compound 1 or a salt thereof or a solvate thereof for the medicament, method, or use according to any one of [1] to [41] wherein the compound 1 or a salt thereof or a solvate thereof is the compound 1.
• the above compound 1 or a salt thereof or a solvate thereof is the above compound 1, and the above molecular targeting agent is a KRAS-G12C selective inhibitor, [1] to [14] and [19] Compound 1 or a salt thereof or a solvate thereof, a molecular targeting agent for use, or use for use in the medicament, method, or use according to any one of [27].
• Compound 1 or a salt thereof or a solvate thereof for the medicament, method, or use according to [53] wherein the KRAS-G12C selective inhibitor is sotorasib or a salt thereof or a solvate thereof A substance, a molecular targeting agent for use, or a use.
• the above compound 1 or a salt thereof or a solvate thereof is the above compound 1, and the above molecular targeting agent is RMC-4550 or a salt thereof or a solvate thereof, [1] to [21] ], [24], [25], and the medicament, method, compound 1 or a salt thereof or a solvate thereof for use, or a molecular target for use according to any one of [32] to [35] agent or use.
• the above-mentioned Compound 1 or a salt thereof or a solvate thereof is the above-mentioned Compound 1, and the above-mentioned molecular targeting agent is TNO155 or a salt thereof or a solvate thereof, [1] to [20], Compound 1 or a salt thereof or a solvate thereof for the medicament, method, or use according to any one of [22], [24], [25], [32] to [34], and [36]; Molecular targeting agent for use or use.
• the above compound 1 or a salt thereof or a solvate thereof is the above compound 1, and the above molecular targeting agent is GDC-1971 or a salt thereof or a solvate thereof, [1] to [20] ], [23] to [25], [32] to [34], and [37] for the medicament, method, and use of Compound 1 or a salt thereof or a solvate thereof; Molecular targeting agent or use for.
• the above Compound 1 or a salt thereof or a solvate thereof is the above Compound 1, and the above molecular targeting agent is bevacizumab, [1] to [25], [38], and [39].
• the above compound 1 or a salt thereof or a solvate thereof is the above compound 1, and the above molecular targeting agent is an anti-PD-L1 antibody, [1] to [25], [40], and Compound 1 or a salt thereof or a solvate thereof for use, a molecular targeting agent for use, or use according to any of [41].
• the above cancers include lung cancer, esophageal cancer, stomach cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, head and neck cancer, and leukemia.
• [65] Compound 1 or for use in the medicament, method, or use according to [63] or [64], wherein the abnormality in the MAPK/ERK pathway is abnormal activation due to increased expression of a protein in the MAPK/ERK pathway. Salts or solvates thereof, molecular targeting agents for use, or uses.
• [69] Contains at least one selected from the group consisting of a KRAS-G12C selective inhibitor, a SHP2 inhibitor, a VEGF inhibitor, and a PD-1 system binding antagonist, in combination with Compound 1 or a salt thereof or a solvate thereof medicines for the treatment or prevention of cancer.
• Compound 1 or a salt thereof or a solvate thereof and at least one selected from the group consisting of a KRAS-G12C selective inhibitor, a SHP2 inhibitor, a VEGF inhibitor, and a PD-1 system binding antagonist A method for treating or preventing cancer.
• Compound 1 or a salt thereof or a solvate thereof For use in the treatment or prevention of cancer in combination with at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists.
• Compound 1 or a salt thereof or a solvate thereof for use in the treatment or prevention of cancer in combination with at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists.
• KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor and PD-1 system for use in cancer treatment or prevention, used in combination with Compound 1 or a salt thereof or a solvate thereof At least one selected from the group consisting of binding antagonists.
• Production of a medicament for treating or preventing cancer which is used in combination with at least one selected from the group consisting of a KRAS-G12C selective inhibitor, a SHP2 inhibitor, a VEGF inhibitor, and a PD-1 system binding antagonist.
• KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor and PD for the production of a medicament for treating or preventing cancer, used in combination with Compound 1 or a salt thereof or a solvate thereof
• KRAS-G12C selection for the use of Compound 1 or a salt thereof or a solvate thereof, for use in the medicament, method, or use according to any one of [68] to [75], wherein are used simultaneously or separately. or the use of at least one selected from the group consisting of a synthetic inhibitor, a SHP2 inhibitor, a VEGF inhibitor, and a PD-1 system binding antagonist.
• At least one selected from the group consisting of the above-mentioned KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist is a KRAS-G12C selective inhibitor, SHP2 inhibitor, or VEGF Compound 1 or a salt thereof or a solvate thereof for use in the medicament, method, or use according to any one of [68] to [77], which is an inhibitor, and a KRAS-G12C selective inhibitor for use; At least one selected from the group consisting of SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, or use thereof.
• KRAS-G12C selective inhibitor is at least one selected from the group consisting of sotorasib, adaglasib, salts thereof, and solvates thereof;
• Method use of Compound 1 or a salt thereof or a solvate thereof, use of a compound selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors and PD-1 system binding antagonists.
• KRAS-G12C selective inhibitor is adagrasib, a salt thereof, or a solvate thereof; Solvates thereof, at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors and PD-1 system binding antagonists, or use.
• the SHP2 inhibitor is at least one selected from the group consisting of RMC-4550, TNO155, SHP099, NSC-87877, RMC-4630, GDC-1971, salts thereof, and solvates thereof, Compound 1 or a salt thereof or a solvate thereof for use in the medicament, method, or use according to any one of [68] to [82], KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF for use At least one selected from the group consisting of inhibitors and PD-1 binding antagonists, or use thereof.
• the SHP2 inhibitor is at least one selected from the group consisting of RMC-4550, TNO155, GDC-1971, salts thereof, and solvates thereof.
• a KRAS-G12C selective inhibitor from Compound 1 or a salt thereof or a solvate thereof, a KRAS-G12C selective inhibitor, a SHP2 inhibitor, a VEGF inhibitor, and a PD-1 system binding antagonist for use in the medicament, method, use, etc.
• the PD-1 system binding antagonist is an anti-PD-L1 antibody at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, or use thereof.
• At least one selected from the group consisting of the KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist is a KRAS-G12C selective inhibitor
• Compound 1 or a salt thereof or a solvate thereof a KRAS-G12C selective inhibitor, a SHP2 inhibitor, a VEGF inhibitor, and a PD-1 system binding antagonist for use; Or use.
• [93] Compound 1 or a salt thereof for the medicament, method, or use according to [90] or [91], wherein the KRAS-G12C selective inhibitor is sotorasib or a salt thereof or a solvate thereof; Solvates thereof, at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors and PD-1 system binding antagonists, or use.
• At least one selected from the group consisting of the KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist is a SHP2 inhibitor, [68] to [89] Compound 1 or a salt thereof or a solvate thereof for use, a KRAS-G12C selective inhibitor, a SHP2 inhibitor, a VEGF inhibitor, and a PD-1 system for use in the medicament, method, and use according to any of At least one selected from the group consisting of binding antagonists, or use.
• the SHP2 inhibitor is at least one selected from the group consisting of RMC-4550, TNO155, SHP099, NSC-87877, RMC-4630, GDC-1971, salts thereof, and solvates thereof, Compound 1 or a salt thereof or a solvate thereof, KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system for use in the medicament, method, and use according to [95] At least one selected from the group consisting of binding antagonists, or use. [97] The SHP2 inhibitor according to [95] or [96], wherein the SHP2 inhibitor is at least one selected from the group consisting of RMC-4550, TNO155, GDC-1971, salts thereof, and solvates thereof.
• a KRAS-G12C selective inhibitor for use in a medicament, method, use At least one selected type or use.
• At least one selected from the group consisting of the KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists is a VEGF inhibitor, [68] to [89] Compound 1 or a salt thereof or a solvate thereof for use, a KRAS-G12C selective inhibitor, a SHP2 inhibitor, a VEGF inhibitor, and a PD-1 system for use in the medicament, method, and use according to any of At least one selected from the group consisting of binding antagonists, or use.
• the VEGF inhibitor is bevacizumab, the medicament, method, compound 1 or a salt thereof or a solvate thereof for use, the KRAS-G12C selective inhibitor for use, At least one selected from the group consisting of SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, or use thereof.
• At least one selected from the group consisting of the KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist is a PD-1 system binding antagonist,
• the PD-1 system binding antagonist is an anti-PD-L1 antibody, Compound 1 or a salt thereof or a solvate thereof for use in the medicament, method, or use according to [103], KRAS for use - At least one selected from the group consisting of G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, or use thereof.
• KRAS for use - At least one selected from the group consisting of G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, or use thereof.
• Salts or solvates thereof at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, or use.
• the above compound 1 or a salt thereof or a solvate thereof is a sodium salt of the above compound 1, and is selected from the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• KRAS-G12C selective inhibitor is sotorasib or a salt thereof or a solvate thereof at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, or use.
• KRAS-G12C selective inhibitor is adagrasib or a salt thereof or a solvate thereof at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, or use.
• the above compound 1 or a salt thereof or a solvate thereof is a sodium salt of the above compound 1, and is selected from the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• Compound 1 or a salt thereof or a solvate thereof for use in any of the medicaments, methods, uses of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors and PD-1 system binding At least one selected from the group consisting of antagonists, or use thereof.
• the above compound 1 or a salt thereof or a solvate thereof is a sodium salt of the above compound 1, and is selected from the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• the above compound 1 or a salt thereof or a solvate thereof is a sodium salt of the above compound 1, and is selected from the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• the above compound 1 or a salt thereof or a solvate thereof is a sodium salt of the above compound 1, and is selected from the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• the above compound 1 or a salt thereof or a solvate thereof is a sodium salt of the above compound 1, and is selected from the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• the above compound 1 or a salt thereof or a solvate thereof is the above compound 1, and is selected from the group consisting of the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• KRAS-G12C selective inhibitor is sotorasib or a salt thereof or a solvate thereof at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, or use.
• KRAS-G12C selective inhibitor is adagrasib or a salt thereof or a solvate thereof at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, or use.
• the above compound 1 or a salt thereof or a solvate thereof is the above compound 1, and is selected from the group consisting of the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• At least one selected from any of [68] to [85], [88], [89], and [95] to [98] is RMC-4550, a salt thereof, or a solvate thereof.
• the described medicament, method, use of Compound 1 or a salt thereof or a solvate thereof, consisting of a KRAS-G12C selective inhibitor, a SHP2 inhibitor, a VEGF inhibitor and a PD-1 system binding antagonist for use At least one selected from the group or use.
• the above compound 1 or a salt thereof or a solvate thereof is the above compound 1, and is selected from the group consisting of the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• At least one selected is GDC-1971 or a salt thereof or a solvate thereof.
• the above compound 1 or a salt thereof or a solvate thereof is the above compound 1, and is selected from the group consisting of the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• the above compound 1 or a salt thereof or a solvate thereof is the above compound 1, and is selected from the group consisting of the above KRAS-G12C selective inhibitor, SHP2 inhibitor, VEGF inhibitor, and PD-1 system binding antagonist.
• cancer is a solid cancer or a blood cancer; At least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists for use, or use.
• the above cancers include lung cancer, esophageal cancer, stomach cancer, colon cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, head and neck cancer, and leukemia.
• Compound 1 or a salt thereof for use in the medicament, method, or use according to any one of [68] to [125] wherein the cancer is a cancer associated with an abnormality in the RAS gene or MAPK/ERK pathway.
• [128] Compound 1 or for use in the medicament, method, or use according to [126] or [127], wherein the abnormality in the MAPK/ERK pathway is abnormal activation due to increased expression of a protein in the MAPK/ERK pathway. Salts thereof or solvates thereof, at least one selected from the group consisting of KRAS-G12C selective inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists for use, or use. [129] Compound 1 for the medicament, method, and use according to any one of [126] to [128], wherein the abnormality in the MAPK/ERK pathway is abnormal activation due to a genetic mutation in the MAPK/ERK pathway.
• KRAS-G12C selective inhibitor SHP2 inhibitor
• VEGF inhibitor VEGF inhibitor
• PD-1 system binding antagonist PD-1 system binding antagonist
• a medicament that exhibits excellent effects in treating or preventing cancer is provided.
• FIG. 1 is an electrophoretic image showing the RAS signal inhibition activity when Compound 1 and sotorasib or adaglasib are used together.
• FIG. 2 is an electrophoretic image showing the RAS signal inhibition activity when Compound 1 and TNO155 are used together.
• FIG. 3 is an electrophoretic image showing the RAS signal inhibition activity when Compound 1 and GDC-1971 are used together.
• FIG. 4 shows the results of isobologram analysis of the cell proliferation inhibitory activity when Compound 1 and sotorasib or adaglasib were used together.
• (a), (b), and (c) of FIG. 5 are diagrams showing the cell proliferation inhibitory activity when Compound 1 and TNO155 are used together against cell line NCI-H2122.
• FIG. 6 shows the results of isobologram analysis of cell proliferation inhibitory activity.
• FIG. 7 shows the cell proliferation inhibitory activity when Compound 1 and RMC-4550 are used in combination against cell line NCI-H2122.
• FIG. 8 shows the results of isobologram analysis of cell proliferation inhibitory activity.
• FIG. 9 shows the results of isobologram analysis of cell proliferation inhibitory activity when Compound 1 and TNO155 are used together against cell line NCI-H1373.
• FIG. 9(a) shows the results of isobologram analysis of cell proliferation inhibitory activity. Note that the broken line in FIG. 9(a) connects the maximum treatment concentration of TNO155 of 10 ⁇ M and the IC 50 of Compound 1 alone.
• (b) is a diagram showing the growth inhibition rate.
• (c) is a diagram showing EOB.
• (a), (b), and (c) of FIG. 10 are diagrams showing the cell proliferation inhibitory activity when Compound 1 and TNO155 are used together against cell line HCC-1171.
• (a) shows the results of isobologram analysis of cell proliferation inhibitory activity.
• (b) is a diagram showing the growth inhibition rate.
• (c) is a diagram showing EOB. (a), (b), and (c) of FIG.
• FIG. 11 are diagrams showing the cell proliferation inhibitory activity when Compound 1 and TNO155 are used together against cell line NCI-H23.
• (a) shows the results of isobologram analysis of cell proliferation inhibitory activity.
• (b) is a diagram showing the growth inhibition rate.
• (c) is a diagram showing EOB.
• (a), (b), and (c) of FIG. 12 are diagrams showing the cell proliferation inhibitory activity when Compound 1 and GDC-1971 are used together against cell line NCI-H1373.
• (a) shows the results of isobologram analysis of cell proliferation inhibitory activity.
• (b) is a diagram showing the growth inhibition rate.
• (c) is a diagram showing EOB. (a), (b), and (c) of FIG.
• FIG. 13 are diagrams showing the cell proliferation inhibitory activity when Compound 1 and GDC-1971 are used together against cell line A-427.
• (a) shows the results of isobologram analysis of cell proliferation inhibitory activity.
• (b) is a diagram showing the growth inhibition rate.
• (c) is a diagram showing EOB.
• (a), (b), and (c) of FIG. 14 are diagrams showing the cell proliferation inhibitory activity when Compound 1 and GDC-1971 are used together against cell line NCI-H1944.
• (a) shows the results of isobologram analysis of cell proliferation inhibitory activity.
• (b) is a diagram showing the growth inhibition rate.
• (c) is a diagram showing EOB. (a), (b), and (c) of FIG.
• FIG. 15 are diagrams showing the cell proliferation inhibitory activity when Compound 1 and GDC-1971 are used together against cell line GP2d.
• (a) shows the results of isobologram analysis of cell proliferation inhibitory activity.
• (b) is a diagram showing the growth inhibition rate.
• (c) is a diagram showing EOB.
• (a), (b), and (c) of FIG. 16 are diagrams showing the cell proliferation inhibitory activity when Compound 1 and GDC-1971 are used together against the cell line HPAC.
• (a) shows the results of isobologram analysis of cell proliferation inhibitory activity.
• (b) is a diagram showing the growth inhibition rate.
• (c) is a diagram showing EOB.
• FIG. 17 is a graph showing the antitumor activity and mouse body weight change rate when the sodium salt of Compound 1 and sotorasib or adaglasib are used in combination.
• FIG. 18 is a graph showing the antitumor activity when the sodium salt of Compound 1 and bevacizumab are used in combination.
• FIG. 19A is a graph showing the antitumor activity when the sodium salt of Compound 1 and TNO155 are used in combination against cell line NCI-H1373.
• FIG. 19B is a graph showing the antitumor activity when the sodium salt of Compound 1 and TNO155 are used in combination against cell line NCI-H358.
• 19C is a graph showing the antitumor activity when the sodium salt of Compound 1 and TNO155 are used in combination against cell line NCI-H441.
• FIG. 20 is a graph showing the antitumor activity when the sodium salt of Compound 1 and anti-PD-L1 antibody are used together. (a) is the result using CT26, and (b) is the result using mLU6054.
• the therapeutic or prophylactic medicament and therapeutic or prophylactic method of the present invention may be administered or applied to humans.
• ⁇ indicating a range includes values at both ends thereof; for example, "A to B” means a range that is greater than or equal to A and less than or equal to B.
• the term “about” when used in conjunction with a numerical value means a range of +10% and 10% of that numerical value.
• the meaning of the term “and/or” includes any combination of "and” and “or” as appropriate.
• A, B, and/or C includes the following seven variations; (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C.
• solvates thereof refer to solvates of compound 1, solvates of molecular targeting agents, solvates of salts of compound 1, or solvates of salts of molecular targeting agents. means.
• One embodiment of the present invention is a medicament for treating or preventing cancer, which contains Compound 1, a salt thereof, or a solvate thereof, and is used in combination with a molecular targeting agent.
• the molecular targeting agent is a MAPK/ERK pathway inhibitor. More preferably, the molecular targeting agent is one selected from the group consisting of KRAS inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists.
• Another embodiment of the present invention is a medicament for treating or preventing cancer, which contains a molecular targeting agent and is used in combination with Compound 1 or a salt thereof or a solvate thereof.
• the molecular targeting agent is a MAPK/ERK pathway inhibitor. More preferably, the molecular targeting agent is one selected from the group consisting of KRAS inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists.
• One embodiment of the present invention is a medicament for treating or preventing cancer, which contains Compound 1, a salt thereof, or a solvate thereof, and is used in combination with a MAPK/ERK pathway inhibitor.
• Another embodiment of the present invention is a medicament for treating or preventing cancer, which contains a MAPK/ERK pathway inhibitor and is used in combination with Compound 1 or a salt thereof or a solvate thereof.
• One embodiment of the present invention is a medicament for treating or preventing cancer, which contains Compound 1, a salt thereof, or a solvate thereof, and is used in combination with a KRAS inhibitor.
• Another embodiment of the present invention is a medicament for treating or preventing cancer, which contains a KRAS inhibitor and is used in combination with Compound 1 or a salt thereof or a solvate thereof.
• One embodiment of the present invention is a medicament for treating or preventing cancer, which contains Compound 1, a salt thereof, or a solvate thereof, and is used in combination with an SHP2 inhibitor.
• Another embodiment of the present invention is a medicament for treating or preventing cancer, which contains a SHP2 inhibitor and is used in combination with Compound 1 or a salt thereof or a solvate thereof.
• the SHP2 inhibitor may be at least one selected from the group consisting of RMC-4550, TNO155, SHP099, NSC-87877, RMC-4630, GDC-1971, salts thereof, and solvates thereof; 4550, TNO155, GDC-1971, salts thereof, and solvates thereof.
• the SHP2 inhibitor is preferably at least one selected from the group consisting of RMC-4550, TNO155, GDC-1971, salts thereof, and solvates thereof; More preferably, it is a product.
• One embodiment of the present invention is a medicament for treating or preventing cancer, which contains Compound 1, a salt thereof, or a solvate thereof, and is used in combination with a VEGF inhibitor.
• Another embodiment of the present invention is a medicament for treating or preventing cancer, which contains a VEGF inhibitor and is used in combination with Compound 1 or a salt thereof or a solvate thereof.
• the VEGF inhibitor may be at least one selected from the group consisting of sorafenib, pazopanib, sunitinib, axitinib, regorafenib and their salts and solvates, and anti-VEGF antibodies, and may be an anti-VEGF antibody. , bevacizumab, ramucirumab, or aflibercept.
• the VEGF inhibitor is preferably an anti-VEGF antibody, more preferably bevacizumab.
• Another embodiment of the present invention is a medicament for treating or preventing cancer, which contains a PD-1 binding antagonist and is used in combination with Compound 1 or a salt thereof or a solvate thereof.
• the PD-1 binding antagonist may be at least one selected from the group consisting of PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists.
• the PD-1 binding antagonist may be an anti-PD-1 antibody, such as MDX-1106 (Nivolumab), MK-3475 (Pembrolizumab, Lambrolizumab), CT-011 (Pidilizumab).
• the PD-L1 binding antagonist may be a small molecule with a molecular weight of 2000 g/mol or less, and may be INCB086550, or a salt thereof, or a solvate thereof, and may be an anti-PD-L1
• the antibody may be YW243.55. It may be at least one selected from the group consisting of S70, Atezolizumab, MPDL3280A, MDX-1105, Avelumab, and MEDI4736 (Durvalumab).
• the PD-L2 binding antagonist may be an anti-PD-L2 antibody or may be an immunoadhesin.
• the PD-1 binding antagonist is preferably a PD-1 binding antagonist or a PD-L1 binding antagonist, more preferably a PD-L1 binding antagonist.
• the PD-1 binding antagonist is preferably an anti-PD-1 antibody, more preferably MDX-1106 (nivolumab) or MK-3475 (pembrolizumab).
• the PD-L1 binding antagonist is an anti-PD-L1 antibody, more preferably atezolizumab.
• One embodiment of the present invention is a medicament for treating or preventing cancer, which contains Compound 1, a salt thereof, or a solvate thereof, and is used in combination with a KRAS-G12C selective inhibitor.
• Another embodiment of the present invention is a medicament for treating or preventing cancer, which contains a KRAS-G12C selective inhibitor and is used in combination with Compound 1 or a salt thereof or a solvate thereof.
• the KRAS-G12C selective inhibitor may be at least one selected from the group consisting of sotorasib, adaglasib, salts thereof, and solvates thereof, and may be sotorasib, a salt thereof, or a solvate thereof. , adagrasib or a salt thereof, or a solvate thereof.
• the KRAS-G12C selective inhibitor is preferably at least one selected from the group consisting of sotorasib, adaglasib, salts thereof, and solvates thereof.
• Compound 1 or a salt thereof or a solvate thereof and a molecular targeting agent may be provided as a kit.
• Yet another embodiment of the present invention can also be referred to as a kit comprising a formulation containing Compound 1 or a salt thereof or a solvate thereof and a molecular targeting agent.
• the above-mentioned medicaments may be provided as a kit.
• Another embodiment of the invention may be a kit containing the medicament.
• Combined use means using two or more components in combination.
• the combination of Compound 1, a salt thereof, or a solvate thereof (hereinafter sometimes referred to as the "first component”) and a molecular targeting agent (hereinafter sometimes referred to as the "second component”) means: "A mode in which the first component and the second component are administered as a single preparation” (i.e., a mode in which the first component and the second component are used together as a combination drug) and "a mode in which the first component and the second component are administered together as a combination drug” and embodiments in which they are administered simultaneously or separately as separate preparations.
• the formulation containing the first component may be administered first, or the formulation containing the second component may be administered first.
• the latter embodiment includes ⁇ a mode in which the first component and the second component are formulated separately and administered at the same time by the same administration route,'' and ⁇ a mode in which the first component and the second component are formulated separately and administered at different times by the same administration route.
• '' ⁇ A mode in which the first component and the second component are formulated separately and administered simultaneously by different administration routes (administered from different sites in the same patient)
• ⁇ A mode in which the first component and the second component are administered separately with the
• the second component may be formulated separately and administered separately by different administration routes at different times.
• both formulations may be mixed immediately before administration.
• "Separately" means that one formulation is administered before or after administration of the other formulation.
• “combined use” can be said to be a method of use in which one component is present in the patient's body while the other component is present in the patient's body. That is, it is preferable to administer the first component and the second component so that they are present simultaneously in the patient's body, for example, in the blood, and a certain formulation is administered to the patient at the same time, or a certain formulation is administered to the patient and then the second component is administered. Embodiments in which other formulations are administered within 48 hours are preferred.
• Compound 1 is 2-(4-cyclopropyl-2-fluoro-anilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]benzamide , 2-(4-cyclopropyl-2-fluoro-anilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]benzamide (CAS number :2677856-11-8).
• the first component may be Compound 1, a salt of Compound 1, a solvate of a salt of Compound 1, or a solvate of Compound 1.
• Examples of the salt of Compound 1 include pharmaceutically acceptable salts, specifically salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; acetic acid, succinic acid, Salts with organic acids such as fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid; salts with alkali metals such as sodium and potassium ; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; salts with amino acids such as arginine, and the like.
• inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid
• acetic acid succinic acid
• Salts with organic acids such as fumaric acid, maleic acid, tartaric acid,
• solvates are not particularly limited as long as Compound 1 forms a single molecular group together with a solvent, but it is formed by a solvent that can be taken (ingested) with administration of a drug. It is a solvate.
• solvates include single solvents such as hydrates, alcohol hydrates (ethanol hydrate, methanol hydrate, 1-propanol hydrate, 2-propanol hydrate, etc.), dimethyl sulfoxide, etc.
• solvates with In addition to solvates with , one molecule of compound 1 and multiple molecules of solvent form a solvate, and one molecule of compound 1 with multiple types of solvents form a solvate. can be mentioned.
• the solvent is water
• the solvate is called a hydrate.
• Solvates are produced, for example, by contacting Compound 1 with a solvent
• salt solvates are produced, for example, by contacting the salt of Compound 1 with a solvent.
• the salts of Compound 1 or the solvates of Compound 1 or the salts of Compound 1 are all active forms, similar to Compound 1 (free form).
• the salt of Compound 1 is preferably a sodium salt.
• Compound 1 can form a sodium salt represented by the following formula (2).
• the molecular targeting agent described below may also be in the form of a salt or solvate as exemplified as the salt of compound 1, and the salt or solvate of the molecular targeting agent may be in the form of a salt or solvate of compound 1. It can be obtained by the manufacturing method exemplified as the method.
• the first component may include crystal polymorphs, but it may be a single crystal form or a mixture thereof.
• the first component also includes an amorphous body.
• the dosage of the first component is preferably 0.0001 to 50 mg (0.0001 to 50 mg/kg/day), more preferably 0.001 to 2 mg/kg/day, per 1 kg of body weight of the subject to whom it is administered. Preferably, 0.002 to 0.2 mg/kg/day is more preferable. When the dose of the first component is within these ranges, the therapeutic or preventive effect on cancer will be more enhanced.
• the first component may be administered, for example, once a day, twice a day, or three times a day, but once a day is more preferable.
• the first component can be produced, for example, according to the method described in International Publication No. 2021/149776.
• molecular targeting agent refers to a drug that has an antitumor effect and specifically inhibits a specific protein.
• the molecular targeting agent does not include Compound 1, its salts, and solvates thereof.
• molecular targeting agents include MAPK/ERK pathway inhibitors, and MAPK/ERK pathway inhibitors can be used as medicines for treating or preventing cancer.
• MAPK/ERK pathway inhibitor refers to inhibitors of targets involved in MAPK/ERK signaling, and includes inhibitors of growth factors and their receptors, as well as kinase inhibitors.
• MAPK/ERK pathway inhibitors include EGFR inhibitors, VEGF inhibitors, SHP2 inhibitors, KRAS inhibitors, NRAS inhibitors, HRAS inhibitors, KRAS-GTP inhibitors, NRAS-GTP inhibitors, HRAS-GTP Mention may be made of inhibitors, KRAS-G12C inhibitors, ERK inhibitors, AKT inhibitors, and MEK inhibitors.
• the molecular targeting agent may be at least one selected from the group consisting of KRAS inhibitors, SHP2 inhibitors, VEGF inhibitors, and PD-1 system binding antagonists, and KRAS inhibitors, SHP2 inhibitors, VEGF inhibitors, or PD-1 system binding antagonists. -1 binding antagonists.
• the KRAS inhibitor may be a KRAS-G12C selective inhibitor.
• the molecular targeting agent may be at least one selected from the group consisting of a KRAS-G12C selective inhibitor, a SHP2 inhibitor, a VEGF inhibitor, and a PD-1 system binding antagonist,
• the agent may be a SHP2 inhibitor, a VEGF inhibitor or a PD-1 system binding antagonist.
• the molecular targeting agent is a KRAS-G12C selective inhibitor.
• the KRAS-G12C selective inhibitor may be at least one selected from the group consisting of sotorasib, adaglasib, salts thereof, and solvates thereof, and may be sotorasib, a salt thereof, or a solvate thereof. , adagrasib or a salt thereof, or a solvate thereof.
• the KRAS-G12C selective inhibitor is preferably at least one selected from the group consisting of sotorasib, adaglasib, salts thereof, and solvates thereof.
• the molecular targeting agent is a SHP2 inhibitor.
• the SHP2 inhibitor may be at least one selected from the group consisting of RMC-4550, TNO155, SHP099, NSC-87877, RMC-4630, GDC-1971, salts thereof, and solvates thereof; 4550, TNO155, GDC-1971, salts thereof, and solvates thereof.
• the SHP2 inhibitor is preferably at least one selected from the group consisting of RMC-4550, TNO155, GDC-1971, salts thereof, and solvates thereof; More preferably, it is a product.
• the VEGF inhibitor may be at least one selected from the group consisting of sorafenib, pazopanib, sunitinib, axitinib, regorafenib and their salts and solvates, and anti-VEGF antibodies, and may be an anti-VEGF antibody. , bevacizumab, ramucirumab, or aflibercept.
• the VEGF inhibitor is preferably an anti-VEGF antibody, more preferably bevacizumab.
• the PD-1 binding antagonist is preferably a PD-1 binding antagonist or a PD-L1 binding antagonist, more preferably a PD-L1 binding antagonist.
• the PD-1 binding antagonist is preferably an anti-PD-1 antibody, more preferably MDX-1106 (nivolumab) or MK-3475 (pembrolizumab).
• the PD-L1 binding antagonist is an anti-PD-L1 antibody, more preferably atezolizumab.
• Molecular targeting agents can be obtained from commercial suppliers or manufactured according to known methods.
• Sotorasib (CAS number: 2296729-00-3, 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1 -(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one is a compound represented by the following formula (3).
• Sotorasib is AMG510 , or Lumakras.
• Adagrasib (CAS number: 2326521-71-3, MRTX849, 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidine-2 -yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile has the following formula: This is a compound represented by (4).
• RMC-4550 (CAS number: 2172651-73-7, 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6 -(2,3-dichlorophenyl)-5-methyl-2-pyrazine methanol) is a compound represented by the following formula (5).
• TNO155 (CAS number: 1801765-04-7, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)- 3-Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine) is a compound represented by the following formula (6).
• SHP099 (CAS number: 1801747-42-1, 6-(4-amino-4-methyl-1-piperidinyl)-3-(2,3-dichlorophenyl)-2-pyrazinamine) is represented by the following formula (7).
• NSC-87877 (CAS number: 56990-57-9, 8-hydroxy-7-[2-(6-sulfo-2-naphthalenyl)diazenyl]-5-quinolinesulfonic acid) is represented by the following formula (8). It is a compound that
• RMC-4630 is a compound described in Non-Patent Document 1.
• Sorafenib (CAS number: 284461-73-0, 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide has the following formula: It is a compound represented by (9). Sorafenib is used as sorafenib tosylate or Nexavar.
• Pazopanib (CAS number: 444731-52-6, 5-[[4-[(2,3-dimethylindazol-6-yl)-methyl-amino]pyrimidin-2-yl]amino]-2-methyl-benzenesulfone Amide is a compound represented by the following formula (10). Pazopanib is used as pazopanib hydrochloride or Votrient.
• Sunitinib (CAS number: 557795-19-4, N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4 -Dimethyl-1H-pyrrole-3-carboxamide is a compound represented by the following formula (11). Sunitinib is used as sunitinib malate or sutent.
• Axitinib (CAS number: 319460-85-0, N-methyl-2-[[3-[(E)-2-(2-pyridyl)vinyl]-1H-indazol-6-yl]sulfanyl]benzamide is It is a compound represented by formula (12).Axitinib is used as an inwriter.
• Regorafenib (CAS number: 755037-03-7, 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluoro-phenoxy]-N-methyl-pyridine-2- carboxamide) is a compound represented by the following formula (13). Regorafenib is used as regorafenib hydrate, or Stivarga.
• Bevacizumab is an antibody designated by the Japanese Accepted Names for Pharmaceuticals (JAN), or CAS Registry number 216974-75-3, or INN name Bevacizumab.
• Bevacizumab is also a recombinant humanized monoclonal antibody, consisting of the complementarity determining region of a mouse anti-human vascular endothelial growth factor (VEGF) monoclonal antibody, a human framework region, and a constant region of human IgG1.
• VEGF vascular endothelial growth factor
• Bevacizumab is produced by Chinese hamster ovary cells.
• Bevacizumab is a glycoprotein (molecular weight: approximately 149,000) consisting of two H chains ( ⁇ 1 chains) consisting of 453 amino acid residues and two L chains ( ⁇ chains) consisting of 214 amino acid residues. . "Bevacizumab” also includes the biosimilar bevacizumab.
• GDC-1971 (CAS number: 2377352-49-1, (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3, 4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidine]-3-amine is a compound represented by the following formula (14).
• the dosage of the molecular target agent is preferably 0.005 to 300 mg/day (0.005 to 300 mg/kg/day), more preferably 0.01 to 250 mg/kg/day per 1 kg of body weight of the subject to be administered. , 0.02 to 200 mg/kg/day is more preferable. When the dose of the molecular target agent is within these ranges, the therapeutic or preventive effect on cancer is further enhanced.
• the number of administrations of the molecular target agent can be, for example, once or more per week, or twice per week.
• the dosage of the first component and the second component is 0.0001 to 50 mg/kg/day for the first component and 0.005 to 300 mg/kg/day for the second component, respectively, per 1 kg of body weight of the subject to be administered.
• the first component is 0.001 to 2 mg/kg/day
• the second component is 0.01 to 250 mg/kg/day
• the first component is 0.002 to 0.2 mg/kg/day.
• the amount of the second component is 0.02 to 200 mg/kg/day.
• the dose and usage method can be adjusted as appropriate while monitoring blood drug concentrations such as AUC and Cmax and the patient's condition.
• the package insert of the molecular target drug can also be referred to.
• administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous, percutaneous absorption), intracisternal, intravaginal, intraperitoneal, and intravesical. These include target or topical (injection, infusion, powder, ointment, gel, or cream) administration and inhalation (oral or nasal spray).
• the dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and non-aqueous non-aqueous solutions filled in containers adapted for subdividing into individual doses. Oral solutions may be mentioned.
• the dosage forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implantation.
• the methods of administration described above are equally applicable to the first and second components.
• the first component and the second component can be used as a medicament and can be administered as a formulation or combination.
• the first component can be administered, for example, by any of the methods described above, and the second component can be administered, for example, by the same or different method as the first component.
• the interval between administration of the first component and the second component can be, for example, an interval of 0 days to 14 days, an interval of 0 days to 10 days, or an interval of 0 days to 7 days.
• the administration interval can be determined using, for example, AUC, Cmax, Tmax, elimination half-life, and the health condition of the subject.
• the first component can be administered orally (tablets, capsules, etc.) and the second component can be administered by drip.
• both the first component and the second component can be administered orally (tablets, capsules, etc.).
• the first component can be administered by infusion and the second component can be administered orally (tablets, capsules, etc.).
• both the first component and the second component can be administered by drip.
• the first component and the second component may be administered at any interval, such as twice a day, once a day, once a week, once every two weeks, etc.
• both the first component and the second component may be administered once a day, in which case they may be administered before, between, or after meals. Before meals, between meals, or after meals may be before meals, between meals, or after meals of breakfast, lunch, dinner, night snack, or snacks. If the interval between administration of the first component and the second component is within 24 hours, both can be administered once a day.
• the first component and the second component are administered twice a day and once a day, once a day and once a day, once a day and once a day, respectively.
• only the administration interval of the second component may be increased or decreased. It is also possible to increase or decrease only the dosing interval.
• the administration of the second component may be started on the same day that the administration of the first component is started, or the administration of the first component and the second component may be started on different days.
• One course of the administration period is 7 days, and the total number of courses can be one or more, and can also be two or more courses.
• each course may be performed consecutively or a drug rest period may be provided.
• a drug rest period may be provided during the course. If necessary, only the first component can be continuously administered and the second component is suspended during the course, or only the first component can be suspended and the second component can be continuously administered.
• the first and second components can also be included in the same tablet, capsule, etc.
• a pharmaceutical preparation is prepared by introducing a pharmaceutically acceptable carrier into an active ingredient such as Compound 1 or a salt thereof, or a solvate thereof, or a molecular targeting agent, and then formulating it by a known method.
• a pharmaceutically acceptable carrier for formulation, commonly used excipients, binders, lubricants, colorants, flavorings, and if necessary stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, Antioxidants and the like can be used, and the formulation can be formulated by conventional methods by blending ingredients that are generally used as raw materials for pharmaceutical preparations.
• active ingredients used in pharmaceuticals can be processed into optimal shapes and properties, ie, dosage forms, according to the method and purpose of use, using known methods.
• Commonly used dosage forms include liquid pharmaceutical preparations (solutions) such as injections, suspensions, emulsions, and eye drops, as well as tablets, powders, granules, granules, coated tablets, capsules, dry syrups, and troches.
• This includes, but is not limited to, solid pharmaceutical preparations (solid preparations) such as tablets and suppositories.
• a preparation containing an active ingredient such as Compound 1, a salt thereof, a solvate thereof, or a molecular targeting agent can be used as the medicament of the present invention.
• the therapeutic or prophylactic medicament of the present invention may be used by mixing either or both of the first component and the second component with a pharmaceutically acceptable additive.
• a pharmaceutically acceptable additive those skilled in the art can appropriately select well-known additives and use a plurality of additives as necessary.
• the additive is selected as appropriate depending on the oral preparation or injection preparation, and may be mixed with water, ethanol, physiological saline, liquid paraffin, surfactant, sucrose, etc., and the resulting mixture is put into capsules. It may be enclosed.
• Cancer can be classified into solid cancers and blood cancers, and both types are composed of abnormal cells that grow uncontrollably.
• Solid cancers form one or multiple masses, while blood cancers circulate throughout the body via the bloodstream.
• Examples of cancer include solid cancers and blood cancers.
• Cancers include, for example, lung cancer, esophageal cancer, stomach cancer, colon cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, head and neck cancer, leukemia, and malignant cancer. It may be at least one selected from the group consisting of lymphoma and multiple myeloma.
• the cancer is at least one type selected from the group consisting of lung cancer, ovarian cancer, colon cancer, and pancreatic cancer.
• the cancer may be a cancer associated with an abnormality in the RAS gene or an abnormality in the MAPK/ERK pathway.
• Abnormal activation of the MAPK/ERK pathway includes abnormal activation of the MAPK/ERK pathway, which is caused by increased expression of proteins present on the MAPK/ERK pathway, and MAPK/ERK pathway abnormality. Examples include abnormal activation of the MAPK/ERK pathway due to mutations in genes encoding proteins present on the pathway, and abnormal activation of the MAPK/ERK pathway due to abnormalities in the RAF gene.
• Abnormality refers to a state in which various chromosomes, genes, proteins, and signal transduction cascades within a cell deviate from their normal functions and controls, and are usually triggered by their homeostatic activation. .
• Abnormal activation refers to a state in which various chromosomes, genes, proteins, and signal cascades within a cell are activated more than in normal cells; for example, one of the causes may be a genetic mutation.
• Cell activation can be measured, for example, by LC/MS-MS-based assays to directly and quantitatively measure the involvement of variants in cells. (Cancer Discov., 2016, 6, 316-329).
• Increased expression of proteins refers to proteins involved in the MAPK/ERK pathway (e.g., KRAS, NRAS, HRAS, KRAS-GTP, NRAS-GTP, HRAS-GTP, ERK, AKT, MEK, pERK, pAKT, and pMEK). ) refers to increased protein synthesis and expression in living cells. Increased protein expression can be confirmed by measuring the protein by Western blotting, immunohistochemical staining (IHC), etc. and comparing it with that of normal cells (Nat.Rev.Drug Discov. , 2020, 19, 533-552, Molecular Cytogenetics, 2015, 8:103).
• IHC immunohistochemical staining
• Gene mutation means that a specific base in a certain base sequence is different from the base in the corresponding wild-type base sequence.
• Cancer treatment in the present invention refers to a reduction in the number of cancer cells in an individual, suppression of cancer cell proliferation, reduction in tumor volume, reduction in tumor weight, cancer cell It means suppressing the metastasis of cancer or improving various symptoms caused by cancer.
• cancer prevention in the present invention refers to preventing an increase in the number of cancer cells due to the re-proliferation of cancer cells that have decreased, and preventing the re-proliferation of cancer cells whose proliferation has been suppressed. , means to prevent the reduced tumor volume or weight from increasing again.
• the molecular targeting agent may be referred to as a concomitant compound.
• the "sodium salt of compound 1" is a compound represented by the above formula (2).
• “sodium salt of compound 1" is abbreviated as "compound 1.”
• Compound 1 (2-(4-cyclopropyl-2-fluoro-anilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]benzamide) and its sodium salt were manufactured according to the method described in International Publication No. 2021/149776.
• Molecularly targeted agents (sotorasib, adaglasib, TNO155, RMC-4550, GDC-1971 and bevacizumab) were supplied by commercial suppliers or manufacturers.
• the anti-PD-L1 antibody was prepared by changing the constant region of a commercially available anti-PD-L1 antibody (BioXCell, clone: 10F.9G2) to a mouse one, and used it.
• Example 1 In vitro RAS signal inhibition activity evaluation
• Single agent treatment of Compound 1, Sotorasib, Adaglasib, TNO155 or GDC-1971 combined treatment of Compound 1 and Sotorasib, combined treatment of Compound 1 and Adagrasib, combined treatment of Compound 1 and TNO155, and combined treatment of Compound 1 and GDC-1971.
• the effects of combined treatment on human cancer cells were evaluated. More specifically, the effects of the above-mentioned single agent treatment and combination treatment on the phosphorylation of MEK and ERK, and the effect on the binding between KRAS and GTP were evaluated by Western blotting in human cancer cells. did.
• Human cancer cells include KRAS mutation-positive human lung cancer cell lines NCI-H2122 (KRAS-G12C mutation), NCI-H1373 (KRAS-G12C mutation), NCI-H441 (KRAS-G12V mutation), and HPAC (KRAS-G12D). (both ATCC) was used. These cells were seeded on a three-dimensional culture plate PrimeSurface (Sumitomo Bakelite) containing a medium. The medium used is shown in Table 2. The plate seeded with cells was cultured at 37° C. in a 5% carbon dioxide gas incubator for 24 hours.
• Plates treated with these single agents or in combination were cultured in a 5% carbon dioxide incubator at 37° C., and cells were collected after 4, 24, or 72 hours had elapsed.
• the collected cells were lysed with Cell Lysis Buffer (Cell Signaling Technology) containing protease and phosphatase inhibitors (ThermoFisher Scientific) to obtain a protein solution.
• Cell Lysis Buffer Cell Signaling Technology
• protease and phosphatase inhibitors ThermoFisher Scientific
• RAS-GTP an activated form of RAS
• Active Ras Pull-Down and Detection Kit ThermoFisher Scientific
• the protein band was chemiluminescent using Chemi-lumi One Super (Nacalai Tesque), and the above band was detected using ChemiDoc Touch Imaging System (Bio-Rad Laboratories).
• Table 1 shows the primary antibody (4°C, overnight reaction) and secondary antibody (room temperature, 45-60 minute reaction) used, and the dilution rate of each antibody.
• the results of Western blotting for evaluating RAS signal inhibition activity are shown in FIGS. 1, 2, and 3.
• KRAS-GTP represents KRAS bound to GTP.
• the degree of suppression of pMEK, pERK, DUSP4, and DUSP6 when treated in combination with Compound 1 and TNO155 or GDC-1971 was stronger than when treated with a single agent, indicating that the suppression was less likely to weaken over time. It was done.
• Example 2 Cell proliferation inhibitory activity evaluation
• Effects of single-agent treatment with Compound 1, Sotorasib, Adagrasib, TNO155, RMC-4550, or GDC-1971, and combined treatment with Compound 1 and these molecular targeting agents (combined compounds) on the proliferation of human cancer cells The effects were evaluated by measuring the amount of ATP in viable cells.
• dilution series were prepared for each with dimethyl sulfoxide (DMSO).
• DMSO dimethyl sulfoxide
• Dimethyl sulfoxide alone or the concomitant compound and/or Compound 1 were dispensed into a U-bottom 96-well plate or a U-bottom 384-well plate using a liquid dispenser Echo (LABCYTE).
• the KRAS mutation-positive human cancer cell line NCI-H2122 listed in Table 2 was added to wells to which only dimethyl sulfoxide was added (dimethyl sulfoxide-treated wells), or to wells to which the concomitant compound and/or compound 1 was added (compound-treated wells).
• NCI-H358, or MIA PaCa-2 all ATCC
• NCI-H1373, NCI-H23, NCI-H1944, A-427, or HPAC all ATCC
• HCC-1171 KCLB
• GP2d ECACC
• Cell proliferation inhibitory activity (%) (1-(T-V 0 )/(V-V 0 )) ⁇ 100...(1)
• T ATP signal value of compound-treated wells after the above-mentioned predetermined period of time
• V ATP signal value of dimethyl sulfoxide-treated wells after the above-mentioned predetermined period of time has elapsed
• V 0 ATP signal value of wells without cell seeding
• FIGS. 4(a) to 4(f) are isobolograms showing the results of cell proliferation inhibitory activity evaluation using cell line NCI-H2122.
• FIGS. 4(c) and 4(d) are isobolograms showing the results of cell proliferation inhibitory activity evaluation using cell line NCI-H358.
• FIGS. 4(e) and 4(f) are isobolograms showing the results of cell proliferation inhibitory activity evaluation using cell line MIA PaCa-2.
• sotorasib was treated as a concomitant compound.
• FIGS. 4(a) was treated as a concomitant compound.
• FIGS. 4(a) to (f) the horizontal axis of the graph is the final concentration of Compound 1 ( ⁇ mol/L), and the vertical axis is the final concentration of sotorasib or adagrasib ( ⁇ mol/L).
• the dashed lines in Figures 4(a)-(f) indicate all combinations of the concentration of Compound 1 and the concentration of Sotorasib or Adaglasib when the interaction between Compound 1 and Sotorasib or Adagrasib is additive. .
• the IC 80 of sotorasib or adaglasib versus the concentration of Compound 1 was plotted graphically. When those plots were located below the broken line of the isobologram, it was determined that there was a synergistic effect when Compound 1 was combined with sotorasib or adaglasib.
• the concentration (IC 50 ) of the combined compound (TNO155, RMC-4550, or GDC-1971 here) or Compound 1 at which the cell proliferation inhibitory activity was 50% was calculated.
• IC 50 was also analyzed by isobologram in the same manner as IC 80 .
• the analysis results using the isobologram are shown in FIGS. 5 to 16 (a).
• Each figure in FIG. 5 shows the results when cell line NCI-H2122 was used and TNO155 was treated as a concomitant compound.
• Each figure in FIG. 6 shows the results when cell line NCI-H358 was used and TNO155 was treated as a concomitant compound.
• FIG. 5 shows the results when cell line NCI-H2122 was used and TNO155 was treated as a concomitant compound.
• FIG. 6 shows the results when cell line NCI-H358 was used and TNO155 was treated as a concomitant compound.
• FIG. 5 shows the results when cell line NCI-H2122 was used and
• FIG. 7 shows the results when cell line NCI-H2122 was used and RMC-4550 was treated as a concomitant compound.
• FIG. 8 shows the results when cell line NCI-H358 was used and RMC-4550 was treated as a concomitant compound.
• FIG. 9 shows the results when cell line NCI-H1373 was used and TNO155 was treated as a concomitant compound.
• FIG. 10 shows the results when cell line HCC-1171 was used and TNO155 was treated as a concomitant compound.
• FIG. 11 shows the results when cell line NCI-H23 was used and TNO155 was treated as a concomitant compound.
• FIG. 11 shows the results when cell line NCI-H23 was used and TNO155 was treated as a concomitant compound.
• FIG. 12 shows the results when cell line NCI-H1373 was used and GDC-1971 was treated as a concomitant compound.
• FIG. 13 shows the results when cell line A-427 was used and treated with GDC-1971 as a concomitant compound.
• FIG. 14 shows the results when cell line NCI-H1944 was used and GDC-1971 was treated as a concomitant compound.
• FIG. 15 shows the results when cell line GP2d was used and treated with GDC-1971 as a concomitant compound.
• FIG. 16 shows the results when the cell line HPAC was used and treated with GDC-1971 as a concomitant compound.
• the plots solid lines and/or dots
• E Bliss The Bliss independence model was used to evaluate the combination effect of Compound 1 with a concomitant compound (here TNO155, RMC-4550, or GDC-1971).
• the bliss index (E Bliss ) was calculated using the following formula (2).
• EA is the cell proliferation inhibitory activity (%) when Compound 1 is treated as a single agent at a certain concentration C.
• E B is the cell proliferation inhibitory activity (%) when the combined compound is treated as a single agent at a certain concentration C.
• E Bliss is a calculated value (theoretical value) when the effect of the combined use of Compound 1 and the concomitant compound is additive.
• E Bliss E A + E B - (E A ⁇ E B ) ⁇ 100...(2)
• Excess over Bliss score (EOB) was determined according to the following formula (3).
• Excess over Bliss score (EOB) is the difference between the cell proliferation inhibition E A+B (%) obtained when compound 1 and the combined compound are treated together and the bliss index obtained by the above formula (2).
• EOB was a positive value, it was determined that there was a synergistic effect.
• EOB E A+B -E Bliss ...(3)
• the EOB is shown in Figures 5 to 16 (c). Since there were many combinations of concentrations that showed positive EOB as a whole, it was shown that the combination of Compound 1 and the concomitant compound had a synergistic growth-inhibiting effect.
• Example 3 In vivo antitumor activity evaluation
• In vivo antitumor activity and when the sodium salt of Compound 1, sotorasib, or adaglasib was administered as a single agent and when the sodium salt of Compound 1 and each of these molecular targeting agents (combined compounds) were administered in combination.
• Weight change rate was evaluated.
• xenografted mice transplanted with KRAS-G12C mutation-positive human cancer cell lines MIA PaCa-2 or NCI-H2122 (both ATCC) were used.
• Xenograft mice were created by subcutaneously transplanting 5 ⁇ 10 6 human cells per nude mouse. After cell transplantation, when the tumor volume reached 200 to 340 mm 3 , the mice were divided into groups of 8 mice.
• the sodium salt of Compound 1 and sotorasib were administered alone or in combination.
• the sodium salt of Compound 1 and/or sotorasib were administered orally once a day for 14 days.
• the sodium salt of compound 1 is 10% DMSO/10% Cremphor EL/15% HP- ⁇ -CD (2-hydroxypropyl- ⁇ -cyclodextrin)/15% Polyethlen Glycol-400/50% Distilled water for injection (solvent A) It was dissolved in and administered. Sotorasib was dissolved in 1% HPMC (hydroxypropyl methyl cellulose)/1% Tween 80/98% distilled water for injection (solvent B) and administered.
• the sodium salt of Compound 1 was administered at 0.25 mg/kg and solvent B was administered at 20 ml/kg.
• sotorasib single agent administration group sotorasib was administered at 10 mg/kg and solvent A at 20 ml/kg.
• the sodium salt of Compound 1 was administered at 0.25 mg/kg and sotorasib was administered at 10 mg/kg.
• solvent A was administered at 20 ml/kg and solvent B was administered at 20 ml/kg.
• the sodium salt of Compound 1, sotorasib, solvent A, and/or solvent B were orally administered once a day for 14 days. After the administration period, a 22-day observation period was established.
• the sodium salt of Compound 1 and adaglasib were administered alone or in combination.
• the sodium salt of Compound 1 and/or adaglasib were administered orally once daily for 21 days.
• the sodium salt of Compound 1 was dissolved in solvent A and administered.
• Adagrasib was administered after being dissolved in 50 mM Citrate buffer (pH 5.0)/10% HP- ⁇ -CD (2-hydroxypropyl- ⁇ -cyclodextrin) (solvent C) prepared with distilled water for injection.
• the sodium salt of Compound 1 was administered at 0.25 mg/kg or 0.75 mg/kg, and solvent C was administered at 20 ml/kg.
• adaglasib single agent administration group adaglasib was administered at 100 mg/kg and solvent A at 10 ml/kg.
• the sodium salt of Compound 1 was administered at 0.25 mg/kg or 0.75 mg/kg and adaglasib was administered at 100 mg/kg.
• solvent A was administered at 10 ml/kg and solvent C was administered at 20 ml/kg.
• the sodium salt of Compound 1, adagrasib, solvent A, and/or solvent C were orally administered once a day for 21 days.
• FIGS. 17(a) and 17(c) The mouse tumor volume was calculated using the following formula (4), and the results of in vivo antitumor activity evaluation are shown in FIGS. 17(a) and 17(c).
• 17(a) and (b) are the results of an experiment using the cell line MIA PaCa-2
• FIGS. 17(c) and (d) are the results of an experiment using the cell line NCI-H2122.
• the vertical axis in FIGS. 17(a) and (c) is tumor volume (mm 3 ), and the horizontal axis is the number of days after cell transplantation.
• Tumor volume (mm 3 ) 1/2 x long axis (mm) x short axis (mm) x short axis (mm)... (4)
• FIGS. 17(b) and (d) show the weight of the mouse based on the weight on the day when the sodium salt of compound 1, the concomitant compound, solvent A, solvent B, and/or solvent C was started. showed the rate of change in body weight.
• the vertical axes in FIGS. 17(b) and (d) are relative body weight change (%), and the horizontal axes are the number of days after cell transplantation.
• FIG. 17(b) no significant weight loss was observed in the single drug administration group and the combination administration group.
• FIG. 17(d) it was confirmed that weight loss was reduced in the combination administration group compared to the single agent administration group.
• Example 4 In vivo antitumor activity evaluation
• the in vivo antitumor activity of the combination of the sodium salt of compound 1 and bevacizumab was demonstrated in nude mice transplanted with the KRAS mutation-positive human cancer cell line NCI-H441 (ATCC) and in the KRAS mutation-positive human cancer cell line OV56 (ECACC). Evaluation was performed using transplanted SCID mice. Each mouse was subcutaneously transplanted with 5 ⁇ 10 6 cells of each cell, and when the tumor volume reached 200 to 300 mm 3 , the mice were divided into groups of 5 mice.
• the sodium salt of Compound 1 and bevacizumab were administered alone or in combination.
• the sodium salt of Compound 1 was dissolved in solvent A and administered.
• Bevacizumab was administered diluted with physiological saline.
• administration was performed as follows.
• the sodium salt of Compound 1 was administered at 0.0625 mg/kg.
• bevacizumab single agent group bevacizumab was administered at 2.5 mg/kg.
• the sodium salt of Compound 1 was administered at 0.0625 mg/kg and bevacizumab was administered at 2.5 mg/kg.
• solvent A was administered at 20 ml/kg.
• the sodium salt of Compound 1 and solvent A were orally administered once a day for 10 days. Bevacizumab was administered by intraperitoneal injection twice weekly.
• administration was performed as follows.
• the sodium salt of Compound 1 was administered at 0.25 mg/kg and physiological saline was administered at 10 ml/kg.
• bevacizumab monotherapy group bevacizumab was administered at 2.5 mg/kg and solvent A at 20 ml/kg.
• the sodium salt of Compound 1 was administered at 0.25 mg/kg and bevacizumab was administered at 2.5 mg/kg.
• solvent A was administered at 20 ml/kg and physiological saline at 10 ml/kg.
• the sodium salt of Compound 1 and solvent A were orally administered once a day for 10 days. Bevacizumab and saline were administered by intraperitoneal injection twice a week.
• FIGS. 18(a) and 18(b) The mouse tumor volume was calculated using formula (4), and the results of in vivo antitumor activity evaluation are shown in FIGS. 18(a) and 18(b).
• FIG. 18(a) shows the results of an experiment using the cell line NCI-H441
• FIG. 18(b) shows the results of an experiment using the cell line OV56.
• the vertical axis in FIGS. 18(a) and (b) is tumor volume (mm 3 ), and the horizontal axis is the number of days after cell transplantation.
• Example 5 In vivo antitumor activity evaluation
• the in vivo antitumor activity of the combination of the sodium salt of Compound 1 and TNO155 was demonstrated in nude mice transplanted with any of the KRAS mutation-positive human cancer cell lines NCI-H1373, NCI-H358, and NCI-H441 (all ATCC). It was evaluated using NCI-H1373 cells, 1 x 10 7 NCI -H358 cells, or 5 x 10 6 NCI-H441 cells were implanted subcutaneously into each mouse, and the tumor volume was determined approximately. Once the mice reached 150-300 mm3 , they were divided into groups of 5 mice.
• the sodium salt of Compound 1 and TNO155 were administered alone or in combination.
• the sodium salt of Compound 1 was dissolved in solvent A and administered.
• TNO155 was diluted with 0.5% Tween 80, 0.5% methyl cellulose (solvent D) prepared with distilled water for injection and administered.
• administration was performed as follows.
• the sodium salt of Compound 1 was administered at a dose of 0.25 mg/kg, and the solvent D was administered at a dose of 10 ml/kg.
• TNO155 single agent administration group TNO155 was administered at 10 mg/kg and 10% DMSO, 5% Cremophor EL (solvent E) prepared with distilled water for injection was administered at 10 ml/kg.
• the sodium salt of Compound 1 was administered at 0.25 mg/kg and TNO155 was administered at 10 mg/kg.
• solvent E was administered at 10 ml/kg and solvent D was administered at 10 ml/kg.
• the sodium salt of Compound 1 and solvent E were orally administered once a day for 30 days.
• TNO155 and solvent D were orally administered twice a day for 30 days.
• FIGS. 19A, 19B, and 19C show the results of in vivo antitumor activity evaluation.
• FIG. 19A shows the results of an experiment using cell line NCI-H1373
• FIG. 19B shows the results of an experiment using cell line NCI-H358
• FIG. 19C shows the results of an experiment using cell line NCI-H441.
• Figure 19C(a) shows the results of an experiment in which the sodium salt of Compound 1 was administered at a dose of 0.125 mg/kg and TNO155 was administered at a dose of 5mg/kg.
• Figure 19C(c) shows the experimental results when the dose of sodium salt of compound 1 was 0.25 mg/kg and the dose of TNO155 was 5 mg.
• FIGS. 19C(d) shows the experimental results where the dose of the sodium salt of Compound 1 was 0.25 mg/kg and the dose of TNO155 was 10 mg/kg.
• Compound 1 represents the single-dose administration group of the sodium salt of Compound 1
• TNO represents the single-dose administration group of TNO155
• Combo represents the single-dose administration group of the sodium salt of Compound 1. 1 and TNO155
• Control represents the Control group.
• the vertical axis of FIGS. 19A, 19B, and 19C is tumor volume (mm 3 ), and the horizontal axis is the number of days after cell transplantation or the start of administration.
• FIG. 19A, FIG. 19B, and FIG. 19C compared to the Control group, the group administered with the sodium salt of Compound 1 alone, the group administered with TNO155 alone, and the group administered with the sodium salt of Compound 1 in combination with TNO155. It was found that the increase in tumor volume was suppressed. Furthermore, in the combination administration group, the degree of suppression of tumor volume increase was greater than in the single agent administration group, indicating that the in vivo antitumor activity is enhanced by the combined use of the sodium salt of Compound 1 and TNO155. It has been shown.
• Example 6 In vivo antitumor activity evaluation
• the in vivo antitumor activity of the combination of sodium salt of compound 1 and anti-PD-L1 antibody was demonstrated in BALB/C mice transplanted with KRAS mutation-positive mouse colon cancer cell line CT26 (Crown Bioscience) and KRAS mutation-positive mouse lung cancer tissue pieces. Evaluation was performed using C57BL/6J mice transplanted with mLU6054 (Crown Bioscience). 5 x 105 CT26 cells or mLU6054 tissue pieces with a diameter of 2-3 mm3 were implanted subcutaneously into each mouse, and when the tumor volume reached approximately 60-85 mm3 , the mice were divided into groups of 8 mice. divided into groups.
• the sodium salt of Compound 1 and anti-PD-L1 antibody were administered alone or in combination.
• the sodium salt of Compound 1 was dissolved in solvent E and administered.
• Anti-PD-L1 antibody was diluted with PBS and administered.
• administration was performed as follows.
• the sodium salt of Compound 1 was administered at 1 mg/kg and PBS was administered at 10 ml/kg.
• anti-PD-L1 antibody monotherapy group anti-PD-L1 antibody was administered at 10 mg/kg and solvent E was administered at 20 ml/kg.
• the sodium salt of Compound 1 was administered at 1 mg/kg and the anti-PD-L1 antibody was administered at 10 mg/kg.
• solvent E was administered at 20 ml/kg and PBS at 10 ml/kg.
• the sodium salt of Compound 1 and solvent E were orally administered once a day for 21 days.
• Anti-PD-L1 antibody and PBS were administered intravenously twice a week for 21 days.
• FIGS. 20(a) and 20(b) The mouse tumor volume was calculated using formula (4), and the results of in vivo antitumor activity evaluation are shown in FIGS. 20(a) and 20(b).
• FIG. 20(a) shows the experimental results using CT26
• FIG. 20(b) shows the experimental results using mLU6054.
• the vertical axis in FIGS. 20(a) and (b) is tumor volume (mm 3 ), and the horizontal axis is the number of days after the start of administration.

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