WO2022247829A1 - 一种治疗癌症的药物组合物及其用途 - Google Patents

一种治疗癌症的药物组合物及其用途 Download PDF

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WO2022247829A1
WO2022247829A1 PCT/CN2022/094725 CN2022094725W WO2022247829A1 WO 2022247829 A1 WO2022247829 A1 WO 2022247829A1 CN 2022094725 W CN2022094725 W CN 2022094725W WO 2022247829 A1 WO2022247829 A1 WO 2022247829A1
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inhibitor
cancer
tautomer
prodrug
hydrate
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French (fr)
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李景
杜武
霍永旭
李兴海
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Hinova Pharmaceuticals Inc
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Hinova Pharmaceuticals Inc
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Priority to JP2023572181A priority Critical patent/JP2024519388A/ja
Priority to KR1020237044496A priority patent/KR20240012542A/ko
Priority to BR112023024596A priority patent/BR112023024596A2/pt
Priority to EP22810554.0A priority patent/EP4349339A4/en
Priority to US18/563,987 priority patent/US20240277710A1/en
Priority to CA3220357A priority patent/CA3220357A1/en
Priority to AU2022282251A priority patent/AU2022282251A1/en
Publication of WO2022247829A1 publication Critical patent/WO2022247829A1/zh
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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
    • A61K31/506—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
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a pharmaceutical composition for treating cancer and its application.
  • Cancer generally refers to all malignant tumors with biological characteristics such as abnormal cell differentiation and proliferation, uncontrolled growth, invasion and metastasis. Every year, a large number of people die from various cancers, which seriously threatens the survival of human beings. At present, the clinical treatment of tumors is still dominated by surgery and chemotherapy drugs, but since the beginning of the 21st century, molecular targeted drug therapy is playing an increasingly important role. Compared with traditional cytotoxic drugs, molecularly targeted drugs, because they target the characteristics of tumor cells different from normal cells, have changed from blind attack to targeted ones. While exerting a strong anti-tumor effect, they reduce the damage to normal organs and tissues Toxic and side effects, thereby improving the quality of life of patients, has become a hot spot in the development of tumor therapeutic drugs.
  • CD44 is a cell surface transmembrane glycoprotein, which is mainly involved in heterogeneous adhesion, that is, the adhesion of tumor cells to host cells and host matrix, and heterogeneous adhesion plays a role in promoting tumor cell invasion and metastasis.
  • Literature “Anti-CD44 antibodies inhibit both mTORC1 and mTORC2: a new rationale supporting CD44-induced AML differentiation therapy” (Merzaban, J, S, et al.
  • CD44 inhibitors are expected to be used in the treatment of cancer. Although CD44 inhibitors showed good anticancer activity, they were found to have high side effects in clinical trials ("CD44V6-targeted imaging of head and neck squamous cell carcinoma: antivody-based approaches", "Hyaluronic acid targeting of CD44 for cancer therapy: from receptor biology to nanomedicine”).
  • FAK Focal adhesion kinase
  • FAK inhibitors as ligands, can compete with ATP to bind to the binding site of FAK receptors, block the information transmission of FAK-mediated growth and proliferation signaling pathways, and lead to The growth and proliferation of malignant tumor cells are inhibited, and even lead to cell death in large doses.
  • FAK inhibitors also have the problem of high toxicity and side effects.
  • the biological role of FAK in the development of cancer is complex, and its effect on cancer treatment is not certain.
  • the object of the present invention is to provide a pharmaceutical composition for treating cancer and its application.
  • the invention provides a pharmaceutical composition for treating cancer, which is composed of FAK inhibitor and CD44 inhibitor.
  • the weight ratio of the FAK inhibitor to the CD44 inhibitor is 1:10-10:1.
  • the FAK inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate: Defactinib, CEP -28122, CEP-37440, TAE226, PF-562271, PF-431396, VS-4718, PF-573228, BI853520, IN10018, APG-2449;
  • the FAK inhibitor is a compound represented by formula I, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate:
  • R 1 and R 2 are independently selected from hydrogen, methyl, and trideuteromethyl
  • the FAK inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate:
  • the FAK inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate:
  • the CD44 inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate, or polypeptide, Or antibodies: Angstrom6, PEP-1, AMC303, Anti-CD44 mAb H4C4, anti-CD44 mAb HI44a, anti-CD44 mAb IM7, anti-CD44 mAb KM201, RO5429083, RG7356, anti-CD44V6 mAb 2F10, anti-CD44V6 mAb U3 , anti-CD44V6 mAb V6B3, anti-CD44V6 mAb VFF18, anti-CD44V6 mAb VFF4, anti-CD44V6 mAb VFF7;
  • the CD44 inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate: AMC303.
  • the molar ratio of the FAK inhibitor to the CD44 inhibitor is 1:82-82:1;
  • the molar ratio of the FAK inhibitor to the CD44 inhibitor is 0.4-81:1.
  • the FAK inhibitor is a compound or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate
  • the CD44 inhibitor is AMC303, or its optical isomer, Or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate
  • the molar ratio of the FAK inhibitor to the CD44 inhibitor is 0.4-81:1;
  • the FAK inhibitor is Defactinib, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the CD44 inhibitor AMC303, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the molar ratio of the FAK inhibitor and CD44 inhibitor 0.4 ⁇ 27:1;
  • the FAK inhibitor is IN10018, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the CD44 inhibitor AMC303, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the molar ratio of the FAK inhibitor and CD44 inhibitor 1:1.
  • the present invention also provides a preparation method of the aforementioned pharmaceutical composition, which includes the following steps: taking the FAK inhibitor and the CD44 inhibitor according to the weight ratio, and mixing them.
  • the present invention also provides the use of the aforementioned pharmaceutical composition in the preparation of medicines for treating cancer;
  • the cancer is solid tumor, mesothelioma, melanoma, prostate cancer, breast cancer, glioblastoma, brain cancer;
  • the solid tumors include mesothelioma, pancreatic cancer, soft tissue tumors, metastatic tumors, non-solid cancers, sarcoma, adenocarcinoma, lung cancer, breast cancer, lymphoma, gastrointestinal tract cancer, genitourinary system cancer, prostate cancer, ovarian cancer
  • the gastrointestinal cancer includes colon cancer
  • the genitourinary system cancer includes kidney, urothelial or testicular tumors
  • the ovarian cancer includes advanced ovarian cancer;
  • the mesothelioma includes neurofibroma, renal cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, KRAS mutant non-small cell lung cancer, liver cancer, thyroid cancer, breast cancer, nervous system tumors, schwannoma, meningioma , neuroma, adenoid cystic carcinoma, ependymoma, ependymal neoplasm, malignant pleuroma, malignant pleural mesothelioma, triplet tumor, negative breast cancer, non-hematological malignancies, melanoma, colorectal cancer , leukemia, adenocarcinoma, solid tumors;
  • the melanoma includes locally advanced melanoma, melanoma caused by locally mutated N-Ras, metastatic malignant cutaneous melanoma;
  • the colorectal cancer includes metastatic colorectal cancer;
  • the leukemia includes acute myeloid Leukemia;
  • the adenocarcinoma includes adenocarcinoma;
  • the solid tumor includes locally advanced solid tumors, metastatic solid tumors, hepatocellular carcinoma;
  • the prostate cancer includes castration-resistant prostate cancer, metastatic castration-resistant prostate cancer;
  • the brain cancers include neuroepithelial tumors, gliomas, astrocytomas, oligodendrogliomas, ependymal and choroid plexus tumors, pineal gland tumors, nerve cell tumors, gangliomas, neuroblastomas, and neuroblastomas.
  • Cytoma poorly differentiated tumor, embryonal tumor, glioblastoma multiforme, medulloblastoma, schwannoma, meningioma, malignant lymphoma, cerebrovascular tumor, malformed scapularis, carpus pharyngeal tumor , Vascular malformations, telangiectasia, pituitary tumors, metastatic tumors.
  • the present invention also provides a pharmaceutical preparation for treating cancer, which is a preparation prepared by taking the aforementioned pharmaceutical composition as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
  • the present invention also provides a combined drug for treating cancer, which contains FAK inhibitors and CD44 inhibitors of the same or different specifications administered simultaneously or separately, and a pharmaceutically acceptable carrier;
  • the weight ratio of the FAK inhibitor to the CD44 inhibitor is 1:10-10:1;
  • the molar ratio of the FAK inhibitor to the CD44 inhibitor is 1:82 to 82:1;
  • the molar ratio of the FAK inhibitor to the CD44 inhibitor is 0.4-81:1.
  • the FAK inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate: Defactinib, CEP -28122, CEP-37440, TAE226, PF-562271, PF-431396, VS-4718, PF-573228, BI853520, IN10018, APG-2449;
  • the FAK inhibitor is a compound represented by formula I, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate:
  • R 1 and R 2 are independently selected from hydrogen, methyl, and trideuteromethyl
  • the FAK inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate:
  • the FAK inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate:
  • the CD44 inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate, or polypeptide, Or antibodies: Angstrom6, PEP-1, AMC303, Anti-CD44 mAb H4C4, anti-CD44 mAb HI44a, anti-CD44 mAb IM7, anti-CD44 mAb KM201, RO5429083, RG7356, anti-CD44V6 mAb 2F10, anti-CD44V6 mAb U3 , anti-CD44V6 mAb V6B3, anti-CD44V6 mAb VFF18, anti-CD44V6 mAb VFF4, anti-CD44V6 mAb VFF7;
  • the CD44 inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate: AMC303.
  • the FAK inhibitor is a compound or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate
  • the CD44 inhibitor is AMC303, or its optical isomer, Or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate
  • the molar ratio of the FAK inhibitor to the CD44 inhibitor is 0.4-81:1;
  • the FAK inhibitor is Defactinib, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the CD44 inhibitor AMC303, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the molar ratio of the FAK inhibitor and CD44 inhibitor 0.4 ⁇ 27:1;
  • the FAK inhibitor is IN10018, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the CD44 inhibitor AMC303, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the molar ratio of the FAK inhibitor and CD44 inhibitor 1:1.
  • the present invention also provides the use of FAK inhibitors and CD44 inhibitors in combination in the preparation of medicines for treating cancer;
  • the weight ratio of the FAK inhibitor to the CD44 inhibitor is 1:10-10:1.
  • the molar ratio of the FAK inhibitor to the CD44 inhibitor is 1:82-82:1;
  • the molar ratio of the FAK inhibitor to the CD44 inhibitor is 0.4-81:1.
  • the FAK inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate: Defactinib, CEP -28122, CEP-37440, TAE226, PF-562271, PF-431396, VS-4718, PF-573228, BI853520, IN10018, APG-2449;
  • the FAK inhibitor is a compound represented by formula I, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate:
  • R 1 and R 2 are independently selected from hydrogen, methyl, and trideuteromethyl
  • the FAK inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate:
  • the FAK inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate:
  • the CD44 inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate, or polypeptide or antibody : Angstrom6, PEP-1, AMC303, Anti-CD44 mAb H4C4, anti-CD44 mAb HI44a, anti-CD44 mAb IM7, anti-CD44 mAb KM201, RO5429083, RG7356, anti-CD44V6 mAb 2F10, anti-CD44V6 mAb U36, - CD44V6 mAb V6B3, anti-CD44V6 mAb VFF18, anti-CD44V6 mAb VFF4, anti-CD44V6 mAb VFF7;
  • the CD44 inhibitor is the following compound, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate: AMC303.
  • the FAK inhibitor is a compound or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate
  • the CD44 inhibitor is AMC303, or its optical isomer, Or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate
  • the molar ratio of the FAK inhibitor to the CD44 inhibitor is 0.4-81:1;
  • the FAK inhibitor is Defactinib, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the CD44 inhibitor AMC303, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the molar ratio of the FAK inhibitor and CD44 inhibitor 0.4 ⁇ 27:1;
  • the FAK inhibitor is IN10018, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the CD44 inhibitor AMC303, or its optical isomer, or its tautomer, or its salt, or its prodrug, or its hydrate, or its solvate; the molar ratio of the FAK inhibitor and CD44 inhibitor 1:1.
  • the cancer is solid tumor, mesothelioma, melanoma, prostate cancer, breast cancer, glioblastoma, brain cancer;
  • the solid tumors include mesothelioma, pancreatic cancer, soft tissue tumors, metastatic tumors, non-solid cancers, sarcoma, adenocarcinoma, lung cancer, breast cancer, lymphoma, gastrointestinal tract cancer, genitourinary system cancer, prostate cancer, ovarian cancer
  • the gastrointestinal cancer includes colon cancer
  • the genitourinary system cancer includes kidney, urothelial or testicular tumors
  • the ovarian cancer includes advanced ovarian cancer;
  • the mesothelioma includes neurofibroma, renal cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, KRAS mutant non-small cell lung cancer, liver cancer, thyroid cancer, breast cancer, nervous system tumors, schwannoma, meningioma , neuroma, adenoid cystic carcinoma, ependymoma, ependymal neoplasm, malignant pleuroma, malignant pleural mesothelioma, triplet tumor, negative breast cancer, non-hematological malignancies, melanoma, colorectal cancer , leukemia, adenocarcinoma, solid tumors;
  • the melanoma includes locally advanced melanoma, melanoma caused by locally mutated N-Ras, metastatic malignant cutaneous melanoma;
  • the colorectal cancer includes metastatic colorectal cancer;
  • the leukemia includes acute myeloid Leukemia;
  • the adenocarcinoma includes adenocarcinoma;
  • the solid tumor includes locally advanced solid tumors, metastatic solid tumors, hepatocellular carcinoma;
  • the prostate cancer includes castration-resistant prostate cancer, metastatic castration-resistant prostate cancer;
  • the brain cancers include neuroepithelial tumors, gliomas, astrocytomas, oligodendrogliomas, ependymal and choroid plexus tumors, pineal gland tumors, nerve cell tumors, gangliomas, neuroblastomas, and neuroblastomas.
  • Cytoma poorly differentiated tumor, embryonal tumor, glioblastoma multiforme, medulloblastoma, schwannoma, meningioma, malignant lymphoma, cerebrovascular tumor, malformed scapularis, carpus pharyngeal tumor , Vascular malformations, telangiectasia, pituitary tumors, metastatic tumors.
  • the combination of the CD44 inhibitor and the FAK inhibitor of the present invention can exert a synergistic effect, significantly improve the inhibitory effect on tumors, reduce toxic and side effects, and overcome drug resistance of tumors, providing a good choice for clinical treatment of cancer.
  • Figure 1 is a histogram of the survival rate of compound 25 and AMC303 combined in A549 cells.
  • Figure 2 is a histogram of the survival rate of Defactinib and AMC303 combined in A549 cells.
  • Fig. 3 is a diagram of compound 25, Defactinib or IN10018 and AMC303 combined in scratch experiment in A549 cells.
  • Fig. 4 is a statistical graph of compound 25, Defactinib or IN10018 and AMC303 combined with scratch experiment in A549 cells.
  • Fig. 5 is a histogram of the survival rate of compound 25 and AMC303 combined in SW620 cells.
  • Figure 6 is a histogram of the survival rate of Defactinib and AMC303 combined in SW620 cells.
  • the raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.
  • the structure of compound 25 is It is prepared according to the method described in the patent with application number 201910373081.2.
  • Defactinib is a commercially available FAK inhibitor.
  • AMC303 is a CD44v6 inhibitor developed by amcure GmbH and purchased.
  • IN10018 is a FAK inhibitor available for purchase.
  • Embodiment 1 the pharmaceutical composition of the present invention inhibits the effect of cancer cell proliferation
  • Non-small cell lung cancer A549 cells in the logarithmic growth phase were seeded in a 96-well culture plate at a concentration of 1.0 ⁇ 10 3 cells/well. And incubate for 24 hours at 37°C, 5% CO 2 concentration and saturated humidity in an incubator. After 24 hours of incubation, the drug FAK inhibitor (compound 25 or Defactinib) and CD44 inhibitor (AMC303) were sequentially added to the 96-well plate. RPMI 1640 cell culture solution containing 10% fetal bovine serum was added to the negative control well with the same volume as the drug.
  • the concentrations of Compound 25 were: 0 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M and 10 ⁇ M.
  • the concentrations of Defactinib were: 0 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M and 10 ⁇ M.
  • the concentrations of AMC303 were: 0 ⁇ M, 0.002 ⁇ M, 0.005 ⁇ M, 0.014 ⁇ M, 0.041 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M and 10 ⁇ M.
  • the above example provides a combined drug for the treatment of non-small cell lung cancer.
  • the experimental results show that the combination of FAK inhibitor (compound 25 or Defactinib) and CD44 inhibitor AMC303 can significantly inhibit the growth and proliferation of non-small cell lung cancer cells. Cancer effect is significantly better than FAK inhibitor (compound 25 or Defactinib) and CD44 inhibitor AMC303 used alone, with synergistic effect.
  • the combined drug of the invention has good clinical application prospects in the field of non-small cell lung cancer treatment.
  • Embodiment 2 the pharmaceutical composition of the present invention inhibits the effect of cancer cell migration
  • the non-small cell lung cancer A549 cells in the logarithmic growth phase were seeded in a 12-well culture plate at a concentration of 1.0 ⁇ 10 6 cells/well. And incubate for 24 hours at 37°C, 5% CO 2 concentration and saturated humidity in an incubator. The cells in the 12-well plate were scratched, 3 scratches per well, the culture medium was discarded after scratching, and then rinsed with PBS to remove floating cells.
  • FAK inhibitor Compound 25, Defactinib or IN10018
  • CD44 inhibitor AMC303
  • Drugs were prepared using serum-free RPMI 1640 cell culture medium containing 20ng/ml HGF. Serum-free RPMI 1640 cell culture solution (containing 20 ng/ml HGF) was added to the negative control well with the same volume as the drug.
  • the concentration of compound 25 is: 0.4 ⁇ M
  • the concentration of Defactinib is: 0.4 ⁇ M
  • the concentration of IN10018 is: 1 ⁇ M
  • AMC303 concentration 1 ⁇ M.
  • Mobility (%) [Scratch Area (0h)-Scratch Area (48h)]/Scratch Area (0h) ⁇ 100%
  • Histograms were made by Prism statistics using mobility and t-tests were performed. If p ⁇ 0.05, there is a significant difference.
  • Embodiment 3 the pharmaceutical composition of the present invention inhibits the effect of cancer cell proliferation
  • Colorectal cancer SW620 cells in the logarithmic growth phase were seeded in 96-well culture plates at a concentration of 1.0 ⁇ 10 3 cells/well. And incubate for 24 hours at 37°C, 5% CO 2 concentration and saturated humidity in an incubator. After 24 hours of incubation, the drug FAK inhibitor (compound 25 or Defactinib) and CD44 inhibitor (AMC303) were sequentially added to the 96-well plate. RPMI 1640 cell culture solution containing 10% fetal bovine serum was added to the negative control well with the same volume as the drug.
  • the concentrations of Compound 25 were: 0 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M and 10 ⁇ M.
  • the concentrations of Defactinib were: 0 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M and 10 ⁇ M.
  • the concentrations of AMC303 were: 0 ⁇ M, 0.002 ⁇ M, 0.005 ⁇ M, 0.014 ⁇ M, 0.041 ⁇ M, 0.123 ⁇ M, 0.370 ⁇ M, 1.111 ⁇ M, 3.333 ⁇ M and 10 ⁇ M.
  • the above example provides a combined drug for the treatment of colorectal cancer.
  • the experimental results show that the combination of FAK inhibitor (compound 25 or Defactinib) and CD44 inhibitor AMC303 can significantly inhibit the growth and proliferation of colorectal cancer cells, and its anticancer effect It is obviously better than FAK inhibitor (compound 25 or Defactinib) and CD44 inhibitor AMC303 used alone, and has synergistic effect.
  • the combined drug of the invention has good clinical application prospects in the field of colorectal cancer treatment.
  • the research of the present invention found that the combination of CD44 inhibitor and FAK inhibitor can play a synergistic effect, significantly improve the inhibitory effect on tumors, and overcome tumor drug resistance, which provides a good choice for clinical treatment of cancer.

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Abstract

一种治疗癌症的药物组合物及其用途，属于医药领域。该药物组合物是由FAK抑制剂和CD44抑制剂组成。还提供了FAK抑制剂和CD44抑制剂联合用药治疗癌症。所述的CD44抑制剂和FAK抑制剂联合用药，能够发挥协同增效的作用，显著提高对肿瘤的抑制效果，降低毒副作用，并克服肿瘤耐药性，为临床治疗癌症提供了良好的选择。

Description

一种治疗癌症的药物组合物及其用途 技术领域
本发明属于医药领域，具体涉及一种治疗癌症的药物组合物及其用途。
背景技术
癌症通常泛指所有恶性肿瘤，具有细胞分化和增殖异常、生长失去控制、浸润性和转移性等生物学特征。每年因为各种癌症死亡人数很多，严重威胁人类的生存。目前肿瘤的临床治疗依然以手术、化疗药物为主，但进入二十一世纪以来分子靶向药物治疗正扮演着越来越重要的角色。分子靶向药物相较于传统的细胞毒性药物，因为以肿瘤细胞不同于正常细胞的特征为靶点，由盲目攻击变为有的放矢，在发挥强大的抗肿瘤作用同时，减少了对正常器官和组织的毒副作用，从而改善患者生存质量，因此成为肿瘤治疗药物研发的热点。
CD44是一种细胞表面跨膜糖蛋白，主要参与异质性粘附，即肿瘤细胞与宿主细胞和宿主基质的粘附，异质性粘附在肿瘤细胞侵袭转移中起促进作用。文献《Anti-CD44 antibodies inhibit both mTORC1 and mTORC2:a new rationale supporting CD44-induced AML differentiation therapy》(Merzaban,J,S,et al.Leukemia:Official journal of the Leukemia Society of America,Leukemia Research Fund,U.K,2016.)发现用抗体抑制CD44，可导致两个参与癌细胞异常生长的主要通路的表达下降：PI3K(磷脂酰肌醇3激酶)通路和mTOR(哺乳动物雷帕霉素靶蛋白)通路。因此CD44抑制剂有望应用于治疗癌症。虽然CD44抑制剂表现出良好的抗癌活性，但在临床试验中发现其具有较高的毒副作用(《CD44V6-targeted imaging of head and neck squamous cell carcinoma:antivody-based approaches》,《Hyaluronic acid targeting of CD44 for cancer therapy:from receptor biology to nanomedicine》)。
局部黏着斑激酶(focal adhesion kinase，FAK)是一种非受体型酪氨酸蛋白激酶，是细胞内重要的骨架蛋白与多种信号通路的关键分子。FAK在肿瘤发生、发展、迁移和侵袭的各个阶段都具有重要作用。目前，FAK被当作潜在的肿瘤治疗靶点，FAK抑制剂作为配体，可与ATP竞争性结合FAK受体的结合位点，阻断FAK介导的生长、增殖信号通路的信息传递，导致恶性肿瘤细胞生长增殖受抑制，甚至在大剂量时导致细胞死亡。但是FAK抑制剂同样存在毒副作用大的问题。而且，随着研究深入，还发现FAK在癌症病情发展中所起的生物学作用是复杂的，其治疗癌症效果并不能确定。
并且，在治疗癌症过程中，耐药性问题一直是一个很大的困扰。如何克服癌细胞耐药性，也是癌症治疗研究的一个难点。目前尚未见将CD44抑制剂和FAK抑制剂联合使用制备治疗癌症的药物，其是否具有治疗癌症的效果，毒副作用是否降低，是否可以克服癌细胞耐药性都有待进一步研究。
发明内容
本发明的目的是提供一种治疗癌症的药物组合物及其用途。
本发明提供了一种治疗癌症的药物组合物，它是由FAK抑制剂和CD44抑制剂组成。
进一步地，所述FAK抑制剂和CD44抑制剂的重量比为1:10～10:1。
进一步地，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018、APG-2449；
或者，所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
Figure PCTCN2022094725-appb-000001
其中，R 1、R 2分别独立选自氢、甲基、三氘代甲基；
或者，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
Figure PCTCN2022094725-appb-000002
Figure PCTCN2022094725-appb-000003
优选地，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
Figure PCTCN2022094725-appb-000004
Defactinib或IN10018。
进一步地，所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物、或多肽、或抗体：Angstrom6、PEP-1、AMC303、Anti-CD44 mAb H4C4、anti-CD44 mAb HI44a、anti-CD44 mAb IM7、anti-CD44 mAb KM201、RO5429083、RG7356、anti-CD44V6 mAb 2F10、anti-CD44V6 mAb U36、anti-CD44V6 mAb V6B3、anti-CD44V6 mAb VFF18、anti-CD44V6 mAb VFF4、anti-CD44V6 mAb VFF7；
优选地，所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：AMC303。
进一步地，所述FAK抑制剂和CD44抑制剂的摩尔比为1:82～82:1；
优选地，所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1。
进一步地，所述FAK抑制剂为化合物
Figure PCTCN2022094725-appb-000005
或 其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1；
或者，所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～27:1；
或者，所述FAK抑制剂为IN10018、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为1:1。
本发明还提供了一种前述的药物组合物的制备方法，它包括如下步骤：按照重量比取FAK抑制剂和CD44抑制剂，混合，即可。
本发明还提供了前述的药物组合物在制备治疗癌症的药物中的用途；
优选地，所述癌症为实体瘤、间皮瘤、黑素瘤、前列腺癌、乳腺癌、胶质母细胞瘤、脑癌；
所述实体瘤包括间皮瘤、胰腺癌、软组织肿瘤、转移瘤、非固体癌、肉瘤、腺癌、肺癌、乳腺癌、淋巴瘤、胃肠道癌、泌尿生殖系统癌、前列腺癌、卵巢癌；所述胃肠道癌包括结肠癌、所述泌尿生殖系统癌包括肾、尿路上皮或睾丸肿瘤；所述卵巢癌包括晚期卵巢癌；
所述间皮瘤包括神经纤维瘤、肾癌、肺癌、小细胞肺癌、非小细胞肺癌、KRAS突变体非小细胞肺癌、肝癌、甲状腺癌、乳腺癌、神经系统肿瘤、神经鞘瘤、脑膜瘤、神经瘤、腺样囊性癌、室管膜瘤、室管膜肿瘤、恶性胸膜瘤、恶性胸膜间皮瘤、三联体瘤、阴性乳腺癌、非血液恶性肿瘤、黑素瘤、结直肠癌、白血病、腺癌、固体肿瘤；
所述黑素瘤包括局部晚期黑素瘤、局部突变的N-Ras引起的黑素瘤、转移性恶性皮肤黑色素瘤；所述结直肠癌包括转移性结直肠癌；所述白血病包括急性髓性白血病；所述腺癌包括腺癌；所述固体肿瘤包括局部晚期实体瘤、转移性实体瘤、肝细胞癌；
所述前列腺癌包括去势抵抗性前列腺癌、转移性去势抵抗性前列腺癌；
所述脑癌包括神经上皮组织肿瘤、脑胶质瘤、星形细胞瘤、少突胶质瘤、室管膜与脉络丛肿瘤、松果体肿瘤、神经细胞肿瘤、神经节细胞瘤、神经母细胞瘤、分化不良的肿瘤、胚胎性肿瘤、多形胶质母细胞瘤、髓母细胞瘤、神经鞘膜瘤、脑膜瘤、恶性淋巴癌、脑血管肿瘤、畸形性胛溜、腕咽賫瘤，血管畸形毛细血管扩张、垂体肿瘤、转移性肿瘤。
本发明还提供了一种治疗癌症的药物制剂，它是由前述的药物组合物为活性成分，加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
本发明还提供了一种治疗癌症的联合用药物，它含有相同或者不同规格 的同时或者分别给药的FAK抑制剂和CD44抑制剂，以及药学上可接受的载体；
优选地，所述FAK抑制剂和CD44抑制剂的重量比为1:10～10:1；
或者，所述FAK抑制剂和CD44抑制剂的摩尔比为1:82～82:1；
更优选地，所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1。
进一步地，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018、APG-2449；
或者，所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
Figure PCTCN2022094725-appb-000006
其中，R 1、R 2分别独立选自氢、甲基、三氘代甲基；
或者，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
Figure PCTCN2022094725-appb-000007
Figure PCTCN2022094725-appb-000008
优选地，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
Figure PCTCN2022094725-appb-000009
Defactinib或IN10018。
进一步地，所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物、或多肽、或抗体：Angstrom6、PEP-1、AMC303、Anti-CD44 mAb H4C4、anti-CD44 mAb HI44a、anti-CD44 mAb IM7、anti-CD44 mAb KM201、RO5429083、RG7356、anti-CD44V6 mAb 2F10、anti-CD44V6 mAb U36、anti-CD44V6 mAb V6B3、anti-CD44V6 mAb VFF18、anti-CD44V6 mAb VFF4、anti-CD44V6 mAb VFF7；
优选地，所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：AMC303。
进一步地，所述FAK抑制剂为化合物
Figure PCTCN2022094725-appb-000010
或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1；
或者，所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～27:1；
或者，所述FAK抑制剂为IN10018、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为1:1。
本发明还提供了FAK抑制剂和CD44抑制剂联用在制备治疗癌症的药物中的用途；
优选地，所述FAK抑制剂和CD44抑制剂的重量比为1:10～10:1。
或，所述FAK抑制剂和CD44抑制剂的摩尔比为1:82～82:1；
更优选地，所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1。
进一步地，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018、APG-2449；
或者，所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
Figure PCTCN2022094725-appb-000011
其中，R 1、R 2分别独立选自氢、甲基、三氘代甲基；
或者，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
Figure PCTCN2022094725-appb-000012
Figure PCTCN2022094725-appb-000013
优选地，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
Figure PCTCN2022094725-appb-000014
Defactinib或IN10018。
进一步地，所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物或多肽或抗体：Angstrom6、PEP-1、AMC303、Anti-CD44 mAb H4C4、anti-CD44 mAb HI44a、anti-CD44 mAb IM7、anti-CD44 mAb KM201、RO5429083、RG7356、anti-CD44V6 mAb 2F10、anti-CD44V6 mAb U36、anti-CD44V6 mAb V6B3、anti-CD44V6 mAb VFF18、anti-CD44V6 mAb VFF4、anti-CD44V6 mAb VFF7；
优选地，所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：AMC303。
进一步地，所述FAK抑制剂为化合物
Figure PCTCN2022094725-appb-000015
或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1；
或者，所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～27:1；
或者，所述FAK抑制剂为IN10018、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为1:1。
进一步地，所述癌症为实体瘤、间皮瘤、黑素瘤、前列腺癌、乳腺癌、胶质母细胞瘤、脑癌；
所述实体瘤包括间皮瘤、胰腺癌、软组织肿瘤、转移瘤、非固体癌、肉瘤、腺癌、肺癌、乳腺癌、淋巴瘤、胃肠道癌、泌尿生殖系统癌、前列腺癌、卵巢癌；所述胃肠道癌包括结肠癌、所述泌尿生殖系统癌包括肾、尿路上皮或睾丸肿瘤；所述卵巢癌包括晚期卵巢癌；
所述间皮瘤包括神经纤维瘤、肾癌、肺癌、小细胞肺癌、非小细胞肺癌、KRAS突变体非小细胞肺癌、肝癌、甲状腺癌、乳腺癌、神经系统肿瘤、神经鞘瘤、脑膜瘤、神经瘤、腺样囊性癌、室管膜瘤、室管膜肿瘤、恶性胸膜瘤、恶性胸膜间皮瘤、三联体瘤、阴性乳腺癌、非血液恶性肿瘤、黑素瘤、结直肠癌、白血病、腺癌、固体肿瘤；
所述黑素瘤包括局部晚期黑素瘤、局部突变的N-Ras引起的黑素瘤、转移性恶性皮肤黑色素瘤；所述结直肠癌包括转移性结直肠癌；所述白血病包括急性髓性白血病；所述腺癌包括腺癌；所述固体肿瘤包括局部晚期实体瘤、转移性实体瘤、肝细胞癌；
所述前列腺癌包括去势抵抗性前列腺癌、转移性去势抵抗性前列腺癌；
所述脑癌包括神经上皮组织肿瘤、脑胶质瘤、星形细胞瘤、少突胶质瘤、室管膜与脉络丛肿瘤、松果体肿瘤、神经细胞肿瘤、神经节细胞瘤、神经母细胞瘤、分化不良的肿瘤、胚胎性肿瘤、多形胶质母细胞瘤、髓母细胞瘤、神经鞘膜瘤、脑膜瘤、恶性淋巴癌、脑血管肿瘤、畸形性胛溜、腕咽賫瘤，血管畸形毛细血管扩张、垂体肿瘤、转移性肿瘤。
本发明CD44抑制剂和FAK抑制剂联合用药，能够发挥协同增效的作用，显著提高对肿瘤的抑制效果，降低毒副作用，并克服肿瘤耐药性，为临床治疗癌症提供了良好的选择。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为化合物25和AMC303在A549细胞中联用生存率柱状图。
图2为Defactinib和AMC303在A549细胞中联用生存率柱状图。
图3为化合物25、Defactinib或IN10018和AMC303在A549细胞中联用划痕实验图。
图4为化合物25、Defactinib或IN10018和AMC303在A549细胞中联用划痕实验统计图。
图5为化合物25和AMC303在SW620细胞中联用生存率柱状图。
图6为Defactinib和AMC303在SW620细胞中联用生存率柱状图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
本发明实施例中，化合物25结构为
Figure PCTCN2022094725-appb-000016
按照申请号为201910373081.2的专利所述方法制备。Defactinib为市售FAK抑制剂。AMC303是amcure GmbH公司开发的CD44v6抑制剂，购买获得。IN10018是一种FAK抑制剂，购买获得。
实施例1、本发明药物组合物抑制癌症细胞增殖的效果
1、实验方法
取处于对数生长期的非小细胞肺癌A549细胞，以1.0×10 3个/孔的浓度接种于96孔培养板中。并于37℃，5％的CO 2浓度及饱和湿度条件的培养箱中孵育24小时。孵育24小时后，将药物FAK抑制剂(化合物25或Defactinib)和CD44抑制剂(AMC303)先后加入96孔板。阴性对照孔加入和药物同体积的含10％胎牛血清的RPMI 1640细胞培养液。
化合物25的浓度为：0μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
Defactinib的浓度为：0μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
AMC303的浓度为：0μM、0.002μM、0.005μM、0.014μM、0.041μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
加入药物共孵育6天后，每孔加入10μL CCK-8，继续培养2.5小时。于酶标仪中按照波长450nm进行各孔吸光度值(OD)测定。按公式计算细胞生长抑制率。抑制率(％)＝(1－加药孔OD值/对照孔OD值)×100％。再按照q＝E a+b/(E a+E b-E a*E b)药物联合指数进行判定。q值判定标准如表1所示：
表1.q值判定标准
Figure PCTCN2022094725-appb-000017
2、实验结果
(1)化合物25和AMC303联合用药(化合物25&AMC303)
化合物25和AMC303联合用药结果如图1所示。由图1可知：当化合物25和AMC303的摩尔比为81：1时，化合物25和AMC303联合用药对 于抑制A549细胞生长有协同增效作用，可用于协同增效治疗非小细胞肺癌。
(2)Defactinib和AMC303联合用药(Defactinib&AMC303)
Defactinib和AMC303联合用药结果如图2所示。由图2可知：当Defactinib和AMC303的摩尔比为27：1时，Defactinib和AMC303联合用药对于抑制A549细胞生长有协同增效作用，可用于协同增效治疗非小细胞肺癌。
上述实施例提供了一种治疗非小细胞肺癌的联合用药物，实验结果说明FAK抑制剂(化合物25或Defactinib)与CD44抑制剂AMC303联合用药可以显著抑制非小细胞肺癌细胞的生长增殖，其抗癌效果明显优于FAK抑制剂(化合物25或Defactinib)和CD44抑制剂AMC303单独使用，具有协同增效作用。本发明的联合用药物在非小细胞肺癌的治疗领域具有很好的临床应用前景。
实施例2、本发明药物组合物抑制癌症细胞迁移的效果
1、实验方法
取处于对数生长期的非小细胞肺癌A549细胞，以1.0×10 6个/孔的浓度接种于12孔培养板中。并于37℃，5％的CO 2浓度及饱和湿度条件的培养箱中孵育24小时。将12孔板中的细胞进行划痕，每孔3道划痕，划痕后吸弃培养基再用PBS漂洗一遍除去漂浮细胞。将FAK抑制剂(化合物25、Defactinib或IN10018)和CD44抑制剂(AMC303)先后加入12孔板。药物均使用含20ng/ml HGF的无血清RPMI 1640细胞培养液进行配制。阴性对照孔加入和药物同体积的无血清的RPMI 1640细胞培养液(含20ng/ml HGF)。
化合物25浓度为：0.4μM；
Defactinib浓度为：0.4μM；
IN10018浓度为：1μM；
AMC303浓度为：1μM。
单独加入4种药物(化合物25、Defactinib、IN10018、AMC303)，或者同时加入化合物25和AMC303(化合物25&AMC303，化合物25浓度为0.4μM，AMC303浓度为1μM)，或者同时加入Defactinib和AMC303(Defactinib&AMC303，Defactinib浓度为0.4μM，AMC303浓度为1μM)，或者同时加入IN10018和AMC303(IN10018&AMC303，IN10018浓度为1μM，AMC303浓度为1μM)，孵育24小时后，吸弃培养基，用PBS漂洗一遍除去漂浮细胞，于显微镜下观察细胞迁移情况，并使用放大倍数为目镜10×物镜10×进行拍照(0h及24h均需拍照)。使用Image J进行图片处理分析细胞迁移率。迁移率计算公式：
迁移率(％)＝[划痕面积(0h)-划痕面积(48h)]/划痕面积(0h)×100％
使用迁移率通过Prism统计制作柱状图并进行t检验。若p＜0.05即有显著差异。
2、实验结果
细胞迁移结果如图3-4和表2所示。
表2.各组细胞迁移结果显著性差异统计结果
药物组合 P值
化合物25&AMC303vs化合物25 0.046
化合物25&AMC303 vs AMC303 0.036
Defactinib&AMC303 vs Defactinib 0.028
Defactinib&AMC303 vs AMC303 0.016
IN10018&AMC303 vs IN10018 0.045
IN10018&AMC303 vs AMC303 0.014
由图3-4以及表2可知：FAK抑制剂(化合物25、Defactinib或IN10018)与CD44抑制剂AMC303联合用药可以显著抑制非小细胞肺癌细胞的迁移，其抗癌效果明显优于FAK抑制剂(化合物25、Defactinib或IN10018)、CD44制剂AMC303单独使用，具有协同增效作用。本发明的联合用药物在非小细胞肺癌的治疗领域具有很好的临床应用前景。
实施例3、本发明药物组合物抑制癌症细胞增殖的效果
1、实验方法
取处于对数生长期的结直肠癌SW620细胞，以1.0×10 3个/孔的浓度接种于96孔培养板中。并于37℃，5％的CO 2浓度及饱和湿度条件的培养箱中孵育24小时。孵育24小时后，将药物FAK抑制剂(化合物25或Defactinib)和CD44抑制剂(AMC303)先后加入96孔板。阴性对照孔加入和药物同体积的含10％胎牛血清的RPMI 1640细胞培养液。
化合物25的浓度为：0μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
Defactinib的浓度为：0μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
AMC303的浓度为：0μM、0.002μM、0.005μM、0.014μM、0.041μM、0.123μM、0.370μM、1.111μM、3.333μM和10μM。
加入药物共孵育6天后，每孔加入10μL CCK-8，继续培养2.5小时。于酶标仪中按照波长450nm进行各孔吸光度值(OD)测定。按公式计算细胞生长抑制率。抑制率(％)＝(1－加药孔OD值/对照孔OD值)×100％。再按照q＝E a+b/(E a+E b-E a*E b)药物联合指数进行判定。q值判定标准如表3所示：
表3.q值判定标准
Figure PCTCN2022094725-appb-000018
2、实验结果
(1)化合物25和AMC303联合用药(化合物25&AMC303)
化合物25和AMC303联合用药结果如图5所示。由图5可知：当化合物25和AMC303的摩尔比为81：1时，化合物25和AMC303联合用药对于抑制SW620细胞生长有协同增效作用，可用于协同增效治疗结直肠癌。
(2)Defactinib和AMC303联合用药(Defactinib&AMC303)
Defactinib和AMC303联合用药结果如图6所示。由图6可知：当Defactinib和AMC303的摩尔比为1：1时，Defactinib和AMC303联合用药对于抑制SW620细胞生长有协同增效作用，可用于协同增效治疗结直肠癌。
上述实施例提供了一种治疗结直肠癌的联合用药物，实验结果说明FAK抑制剂(化合物25或Defactinib)与CD44抑制剂AMC303联合用药可以显著抑制结直肠癌细胞的生长增殖，其抗癌效果明显优于FAK抑制剂(化合物25或Defactinib)和CD44抑制剂AMC303单独使用，具有协同增效作用。本发明的联合用药物在结直肠癌的治疗领域具有很好的临床应用前景。
综上，本发明研究发现CD44抑制剂和FAK抑制剂联合用药，能够发挥协同增效的作用，显著提高对肿瘤的抑制效果，并克服肿瘤耐药性，为临床治疗癌症提供了良好的选择。

Claims (18)

  1. 一种治疗癌症的药物组合物，其特征在于：它是由FAK抑制剂和CD44抑制剂组成。
  2. 根据权利要求1所述的药物组合物，其特征在于：所述FAK抑制剂和CD44抑制剂的重量比为1:10～10:1。
  3. 根据权利要求1或2所述的药物组合物，其特征在于：所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018、APG-2449；
    或者，所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
    Figure PCTCN2022094725-appb-100001
    其中，R 1、R 2分别独立选自氢、甲基、三氘代甲基；
    或者，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
    Figure PCTCN2022094725-appb-100002
    Figure PCTCN2022094725-appb-100003
    优选地，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
    Figure PCTCN2022094725-appb-100004
    Defactinib或IN10018。
  4. 根据权利要求1或2所述的药物组合物，其特征在于：所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物、或多肽、或抗体：Angstrom6、PEP-1、AMC303、Anti-CD44 mAb H4C4、anti-CD44 mAb HI44a、anti-CD44 mAb IM7、anti-CD44 mAb KM201、RO5429083、RG7356、anti-CD44V6 mAb 2F10、anti-CD44V6 mAb U36、anti-CD44V6 mAb V6B3、anti-CD44V6 mAb VFF18、anti-CD44V6 mAb VFF4、anti-CD44V6 mAb VFF7；
    优选地，所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：AMC303。
  5. 根据权利要求1或2所述的药物组合物，其特征在于：所述FAK抑制剂和CD44抑制剂的摩尔比为1:82～82:1；
    优选地，所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1。
  6. 根据权利要求1或2所述的药物组合物，其特征在于：所述FAK抑 制剂为化合物
    Figure PCTCN2022094725-appb-100005
    或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1；
    或者，所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～27:1；
    或者，所述FAK抑制剂为IN10018、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为1:1。
  7. 一种权利要求1～6任一项所述的药物组合物的制备方法，其特征在于：它包括如下步骤：按照重量比取FAK抑制剂和CD44抑制剂，混合，即可。
  8. 权利要求1～6任一项所述的药物组合物在制备治疗癌症的药物中的用途；
    优选地，所述癌症为实体瘤、间皮瘤、黑素瘤、前列腺癌、乳腺癌、胶质母细胞瘤、脑癌；
    所述实体瘤包括间皮瘤、胰腺癌、软组织肿瘤、转移瘤、非固体癌、肉瘤、腺癌、肺癌、乳腺癌、淋巴瘤、胃肠道癌、泌尿生殖系统癌、前列腺癌、卵巢癌；所述胃肠道癌包括结肠癌、所述泌尿生殖系统癌包括肾、尿路上皮或睾丸肿瘤；所述卵巢癌包括晚期卵巢癌；
    所述间皮瘤包括神经纤维瘤、肾癌、肺癌、小细胞肺癌、非小细胞肺癌、KRAS突变体非小细胞肺癌、肝癌、甲状腺癌、乳腺癌、神经系统肿瘤、神经鞘瘤、脑膜瘤、神经瘤、腺样囊性癌、室管膜瘤、室管膜肿瘤、恶性胸膜瘤、恶性胸膜间皮瘤、三联体瘤、阴性乳腺癌、非血液恶性肿瘤、黑素瘤、结直肠癌、白血病、腺癌、固体肿瘤；
    所述黑素瘤包括局部晚期黑素瘤、局部突变的N-Ras引起的黑素瘤、转移性恶性皮肤黑色素瘤；所述结直肠癌包括转移性结直肠癌；所述白血病包括急性髓性白血病；所述腺癌包括腺癌；所述固体肿瘤包括局部晚期实体瘤、转移性实体瘤、肝细胞癌；
    所述前列腺癌包括去势抵抗性前列腺癌、转移性去势抵抗性前列腺癌；
    所述脑癌包括神经上皮组织肿瘤、脑胶质瘤、星形细胞瘤、少突胶质瘤、室管膜与脉络丛肿瘤、松果体肿瘤、神经细胞肿瘤、神经节细胞瘤、神经母细胞瘤、分化不良的肿瘤、胚胎性肿瘤、多形胶质母细胞瘤、髓母细胞瘤、 神经鞘膜瘤、脑膜瘤、恶性淋巴癌、脑血管肿瘤、畸形性胛溜、腕咽賫瘤，血管畸形毛细血管扩张、垂体肿瘤、转移性肿瘤。
  9. 一种治疗癌症的药物制剂，其特征在于：它是由权利要求1～6任一项所述的药物组合物为活性成分，加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
  10. 一种治疗癌症的联合用药物，其特征在于：它含有相同或者不同规格的同时或者分别给药的FAK抑制剂和CD44抑制剂，以及药学上可接受的载体；
    优选地，所述FAK抑制剂和CD44抑制剂的重量比为1:10～10:1；
    或者，所述FAK抑制剂和CD44抑制剂的摩尔比为1:82～82:1；
    更优选地，所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1。
  11. 根据权利要求10所述的联合用药物，其特征在于：所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018、APG-2449；
    或者，所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
    Figure PCTCN2022094725-appb-100006
    其中，R 1、R 2分别独立选自氢、甲基、三氘代甲基；
    或者，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
    Figure PCTCN2022094725-appb-100007
    Figure PCTCN2022094725-appb-100008
    优选地，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
    Figure PCTCN2022094725-appb-100009
    Defactinib或IN10018。
  12. 根据权利要求10所述的联合用药物，其特征在于：所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物、或多肽、或抗体：Angstrom6、PEP-1、AMC303、Anti-CD44 mAb H4C4、anti-CD44 mAb HI44a、anti-CD44 mAb IM7、anti-CD44 mAb KM201、RO5429083、RG7356、anti-CD44V6 mAb 2F10、anti-CD44V6 mAb U36、anti-CD44V6 mAb V6B3、anti-CD44V6 mAb VFF18、anti-CD44V6 mAb VFF4、anti-CD44V6 mAb VFF7；
    优选地，所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：AMC303。
  13. 根据权利要求10～12任一项所述的药物组合物，其特征在于：所述FAK抑制剂为化合物
    Figure PCTCN2022094725-appb-100010
    或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑 制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1；
    或者，所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～27:1；
    或者，所述FAK抑制剂为IN10018、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为1:1。
  14. FAK抑制剂和CD44抑制剂联用在制备治疗癌症的药物中的用途；
    优选地，所述FAK抑制剂和CD44抑制剂的重量比为1:10～10:1；
    或，所述FAK抑制剂和CD44抑制剂的摩尔比为1:82～82:1；
    更优选地，所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1。
  15. 根据权利要求14所述的用途，其特征在于：所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：Defactinib、CEP-28122、CEP-37440、TAE226、PF-562271、PF-431396、VS-4718、PF-573228、BI853520、IN10018、APG-2449；
    或者，所述FAK抑制剂为式I所示化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
    Figure PCTCN2022094725-appb-100011
    其中，R 1、R 2分别独立选自氢、甲基、三氘代甲基；
    或者，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
    Figure PCTCN2022094725-appb-100012
    优选地，所述FAK抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：
    Figure PCTCN2022094725-appb-100013
    Defactinib或IN10018。
  16. 根据权利要求14所述的用途，其特征在于：所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物或多肽或抗体：Angstrom6、PEP-1、AMC303、Anti-CD44mAb H4C4、anti-CD44 mAb HI44a、anti-CD44 mAb IM7、anti-CD44 mAb KM201、RO5429083、RG7356、anti-CD44V6 mAb 2F10、anti-CD44V6 mAb U36、anti-CD44V6 mAb V6B3、anti-CD44V6 mAb VFF18、anti-CD44V6 mAb  VFF4、anti-CD44V6 mAb VFF7；
    优选地，所述CD44抑制剂为如下化合物、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物：AMC303。
  17. 根据权利要求14～16任一项所述的用途，其特征在于：所述FAK抑制剂为化合物
    Figure PCTCN2022094725-appb-100014
    或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～81:1；
    或者，所述FAK抑制剂为Defactinib、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为0.4～27:1；
    或者，所述FAK抑制剂为IN10018、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述CD44抑制剂为AMC303、或其光学异构体、或其互变异构体、或其盐、或其前药、或其水合物、或其溶剂合物；所述FAK抑制剂和CD44抑制剂的摩尔比为1:1。
  18. 根据权利要求14～16任一项所述的用途，其特征在于：所述癌症为实体瘤、间皮瘤、黑素瘤、前列腺癌、乳腺癌、胶质母细胞瘤、脑癌；
    所述实体瘤包括间皮瘤、胰腺癌、软组织肿瘤、转移瘤、非固体癌、肉瘤、腺癌、肺癌、乳腺癌、淋巴瘤、胃肠道癌、泌尿生殖系统癌、前列腺癌、卵巢癌；所述胃肠道癌包括结肠癌、所述泌尿生殖系统癌包括肾、尿路上皮或睾丸肿瘤；所述卵巢癌包括晚期卵巢癌；
    所述间皮瘤包括神经纤维瘤、肾癌、肺癌、小细胞肺癌、非小细胞肺癌、KRAS突变体非小细胞肺癌、肝癌、甲状腺癌、乳腺癌、神经系统肿瘤、神经鞘瘤、脑膜瘤、神经瘤、腺样囊性癌、室管膜瘤、室管膜肿瘤、恶性胸膜瘤、恶性胸膜间皮瘤、三联体瘤、阴性乳腺癌、非血液恶性肿瘤、黑素瘤、结直肠癌、白血病、腺癌、固体肿瘤；
    所述黑素瘤包括局部晚期黑素瘤、局部突变的N-Ras引起的黑素瘤、转移性恶性皮肤黑色素瘤；所述结直肠癌包括转移性结直肠癌；所述白血病包括急性髓性白血病；所述腺癌包括腺癌；所述固体肿瘤包括局部晚期实体瘤、转移性实体瘤、肝细胞癌；
    所述前列腺癌包括去势抵抗性前列腺癌、转移性去势抵抗性前列腺癌；
    所述脑癌包括神经上皮组织肿瘤、脑胶质瘤、星形细胞瘤、少突胶质瘤、室管膜与脉络丛肿瘤、松果体肿瘤、神经细胞肿瘤、神经节细胞瘤、神经母细胞瘤、分化不良的肿瘤、胚胎性肿瘤、多形胶质母细胞瘤、髓母细胞瘤、神经鞘膜瘤、脑膜瘤、恶性淋巴癌、脑血管肿瘤、畸形性胛溜、腕咽賫瘤， 血管畸形毛细血管扩张、垂体肿瘤、转移性肿瘤。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008129380A1 (en) * 2007-04-18 2008-10-30 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
WO2011109678A1 (en) * 2010-03-05 2011-09-09 Angstrom Pharmaceuticals, Inc. Modulation of intracellular signaling
CN106146406A (zh) * 2016-02-23 2016-11-23 深圳市塔吉瑞生物医药有限公司 一种取代的二氨基嘧啶类化合物及包含该化合物的组合物及其用途
CN111377871A (zh) * 2018-12-27 2020-07-07 成都海创药业有限公司 一种fak抑制剂及其联合用药物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150071918A1 (en) * 2012-05-09 2015-03-12 H. Lee Moffitt Cancer Center And Research Institute, Inc. Peptides for the treatment of cancer
EP2954933A1 (en) * 2014-06-10 2015-12-16 3B Pharmaceuticals GmbH Conjugate comprising a neurotensin receptor ligand
CN106349158B (zh) * 2016-08-03 2020-02-28 杭州市西溪医院 一种c-Met小分子抑制剂、含其的药物组合物及其药学应用
ES2973832T3 (es) * 2019-10-18 2024-06-24 Forty Seven Inc Terapias combinadas para el tratamiento de síndromes mielodisplásicos y leucemia mieloide aguda

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008129380A1 (en) * 2007-04-18 2008-10-30 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
WO2011109678A1 (en) * 2010-03-05 2011-09-09 Angstrom Pharmaceuticals, Inc. Modulation of intracellular signaling
CN106146406A (zh) * 2016-02-23 2016-11-23 深圳市塔吉瑞生物医药有限公司 一种取代的二氨基嘧啶类化合物及包含该化合物的组合物及其用途
CN111377871A (zh) * 2018-12-27 2020-07-07 成都海创药业有限公司 一种fak抑制剂及其联合用药物

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
E. CALVO , P.G. AFTIMOS , A. AZARO , M.J. DE MIGUEL , C. JUNGELS , J. ZERON-MEDINA CUAIRAN , P.G. NUCIFORO , P. EHMER , A. MARTIN : "First-in-Human, First-in-Class Study of the CD44v6 Inhibitor AMC303 as Monotherapy in Patients with Advanced Epithelial Tumors.", ANNALS OF ONCOLOGY, vol. 29, no. Suppelement 8, 1 October 2018 (2018-10-01), pages 1 - 1, XP093008398, DOI: 10.1093/annonc/mdy279.398 *
MERZABAN, J, S ET AL.: "Leukemia: Official journal of the Leukemia Society of America", 2016, LEUKEMIA RESEARCH FUND
See also references of EP4349339A4
ZOU L; SONG X; YI T; LI S; DENG H; CHEN X; LI Z; BAI Y; ZHONG Q; WEI Y; ZHAO X: "Administration of PLGA nanoparticles carrying shRNA against focal adhesion kinase and CD44 results in enhanced antitumor effects against ovarian cancer", CANCER GENE THERAPY, vol. 20, no. 4, 15 March 2013 (2013-03-15), New York, pages 242 - 250, XP037761545, ISSN: 0929-1903, DOI: 10.1038/cgt.2013.12 *

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