WO2024041527A1 - Fak抑制剂及微管抑制剂的药物组合及用途 - Google Patents

Fak抑制剂及微管抑制剂的药物组合及用途 Download PDF

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WO2024041527A1
WO2024041527A1 PCT/CN2023/114225 CN2023114225W WO2024041527A1 WO 2024041527 A1 WO2024041527 A1 WO 2024041527A1 CN 2023114225 W CN2023114225 W CN 2023114225W WO 2024041527 A1 WO2024041527 A1 WO 2024041527A1
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cancer
inhibitor
fak
microtubule
immune checkpoint
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English (en)
French (fr)
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张宝袁
刘学彬
高家明
张平
庞然
王在琪
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应世生物科技(南京)有限公司
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to focal adhesion kinase (Focal Adhesion Kinase, FAK) inhibitors combined with other drugs to treat tumors.
  • focal adhesion kinase Fecal Adhesion Kinase, FAK
  • ICD Immunogenic cell death
  • ER stress endoplasmic reticulum stress
  • oxidative stress reactive oxygen species stress
  • DAMPs damage-associated molecular patterns
  • This type of DAMPs will be specifically recognized by pattern recognition receptors on Antigen-presenting cells (APCs) in the body, induce the maturation, differentiation and activation of APCs, and gradually present them to immune cells such as effector T cells, thereby It causes immune cells to generate antigen memory, and when tumor cells from the same source are found again, the immune cells will specifically recognize and kill the tumor cells.
  • the new tumor-specific immune response initiated by ICD can increase sensitivity to immune checkpoint inhibitors (Immuno-checkpoint inhibitors, ICI), thus enhancing the effect of immune checkpoint inhibitors and producing immune Memory for durable antitumor responses.
  • FAK also known as protein tyrosine kinase 2 (PTK2), is a non-receptor tyrosine kinase and a key component of the focal adhesion complex. FAK plays an important role in mediating integrin and growth factor signaling to regulate tumor cell invasion, proliferation, and survival.
  • PTK2 protein tyrosine kinase 2
  • Microtubules are a dynamic filamentous cytoskeletal protein and the main molecule of centrioles. Microtubules The ordered dynamic changes of fibers are an important guarantee for cell mitosis. Microtubule inhibitors bind to tubulin to promote or inhibit the assembly of microtubules, interfere with the normal structure and function of the spindle composed of microtubules, interfere with cell mitosis, inhibit cell proliferation, and exert clear anti-tumor effects. Anti-tumor drugs targeting microtubules have become an important aspect of current anti-tumor drug research. There are currently many microtubule inhibitors on the market, including taxanes and Eribulin.
  • Taxoid drugs include paclitaxel extracted from natural tree bark, synthetic docetaxel, and now albumin paclitaxel.
  • Taxane drugs are M-phase cycle-specific drugs that promote the polymerization of tubules into stable microtubules and inhibit their polymerization, thereby significantly reducing the number of tubules and destroying the microtubule network structure.
  • Eribulin is a synthetic analog of halichondrin B, which inhibits microtubule depolymerization, thereby causing G2/M blockage of the cell cycle and destroying the mitotic spindle, ultimately leading to cell apoptosis.
  • Taxanes and eribulin are commonly used clinical chemotherapy drugs. However, some resistance will develop after taking it for a period of time.
  • One aspect of the present disclosure provides the use of FAK inhibitors, microtubule inhibitors, and immune checkpoint inhibitors in the preparation of a medicament for treating tumors in a subject.
  • Yet another aspect of the present disclosure provides a pharmaceutical combination product of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor for use in treating tumors in a subject.
  • Yet another aspect of the present disclosure provides a method of treating tumors, the method comprising administering a therapeutically effective amount of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor to a subject in need thereof.
  • kit or pharmaceutically acceptable composition comprising: (a) a FAK inhibitor; (b) a microtubule inhibitor; and (c) an immune checkpoint inhibitor.
  • Yet another aspect of the present disclosure provides the use of a FAK inhibitor and a microtubule inhibitor in the preparation of a medicament for treating tumors, wherein the FAK inhibitor is used to enhance immunogenic cell death induced by the microtubule inhibitor. .
  • Yet another aspect of the present disclosure provides FAK inhibitors for use in the treatment of tumors to enhance microtubule inhibitor-induced immunogenic cell death.
  • Yet another aspect of the present disclosure provides a method of treating tumors, the method comprising administering a therapeutically effective amount of a FAK inhibitor and a microtubule inhibitor to a subject in need thereof, wherein the FAK inhibitor is used Enhancement of immunogenic cell death induced by the microtubule inhibitors.
  • Yet another aspect of the present disclosure provides the use of FAK inhibitors, microtubule inhibitors and immune checkpoint inhibitors in the preparation of drugs for combined treatment of tumors.
  • Yet another aspect of the present disclosure provides the use of a FAK inhibitor in the preparation of a drug for use in combination with a microtubule inhibitor and an immune checkpoint inhibitor to treat tumors.
  • Yet another aspect of the present disclosure provides the use of a microtubule inhibitor in the preparation of a drug for use in combination with a FAK inhibitor and an immune checkpoint inhibitor to treat tumors.
  • Yet another aspect of the present disclosure provides the use of an immune checkpoint inhibitor in the preparation of a drug for use in combination with a FAK inhibitor and a microtubule inhibitor to treat tumors.
  • Yet another aspect of the disclosure provides the use of a FAK inhibitor in the preparation of a medicament for the treatment of tumors in combination with a microtubule inhibitor and an immune checkpoint inhibitor.
  • Yet another aspect of the present disclosure provides the use of a microtubule inhibitor in the preparation of a medicament for the treatment of tumors in combination with a FAK inhibitor and an immune checkpoint inhibitor.
  • Yet another aspect of the present disclosure provides the use of an immune checkpoint inhibitor in the preparation of a medicament for the treatment of tumors in combination with a FAK inhibitor and a microtubule inhibitor.
  • kits which includes: a FAK inhibitor; and instructions indicating that the FAK inhibitor can be used to treat tumors in combination with microtubule inhibitors and immune checkpoint inhibitors.
  • kits which includes: a microtubule inhibitor; and instructions indicating that the microtubule inhibitor can be used to treat tumors in combination with a FAK inhibitor and an immune checkpoint inhibitor.
  • kits which includes: an immune checkpoint inhibitor; and instructions indicating that the immune checkpoint inhibitor can be used to treat tumors in combination with a FAK inhibitor and a microtubule inhibitor.
  • Another aspect of the present disclosure provides a method of treating a tumor, comprising administering a therapeutically effective amount of a FAK inhibitor and a microtubule inhibitor to a subject in need thereof.
  • Yet another aspect of the present disclosure provides a pharmaceutical combination of a FAK inhibitor and a microtubule inhibitor for use in treating tumors in a subject in need thereof.
  • Yet another aspect of the present disclosure provides the use of a FAK inhibitor and a microtubule inhibitor in the preparation of a combination drug for treating tumors.
  • Another aspect of the present disclosure provides FAK inhibitors for use in treating tumors with microtubule inhibitors. Use in combination drugs.
  • Yet another aspect of the present disclosure provides the use of a microtubule inhibitor in the preparation of a medicament for use in combination with a FAK inhibitor to treat tumors.
  • Yet another aspect of the present disclosure provides the use of a FAK inhibitor and a microtubule inhibitor in the preparation of a medicament for combined treatment of tumors.
  • Yet another aspect of the present disclosure provides the use of a FAK inhibitor in the preparation of a medicament for the treatment of tumors in combination with a microtubule inhibitor.
  • Yet another aspect of the present disclosure provides the use of a microtubule inhibitor in the preparation of a medicament for the treatment of tumors in combination with a FAK inhibitor.
  • kits which includes: a FAK inhibitor; and instructions indicating that the FAK inhibitor can be used to treat tumors in combination with a microtubule inhibitor.
  • kits which includes: a microtubule inhibitor; and instructions indicating that the microtubule inhibitor can be used to treat tumors in combination with a FAK inhibitor.
  • the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt is further preferably IN10018 or a pharmaceutically acceptable salt thereof, especially IN10018 tartrate.
  • the structure of IN10018 is as follows:
  • the Defactinib is also called defatinib, and its CAS number is 1345713-71-4; the CAS number of GSK2256098 is 1224887-10-8.
  • the CAS number of PF-00562271 is 717907-75-0; the CAS number of VS-4718 is 1061353-68-1; the APG-2449 is developed by Ascentage Pharmaceuticals; the CAS number of AMP945 is 1393653- 34-3.
  • the microtubule inhibitor is taxane, Eribulin, Ixempra or vinca alkaloids.
  • the microtubule inhibitor is a taxane drug.
  • the taxane drugs are Docetaxel, Paclitaxel, Cabazitaxel or Cephalomannine, preferably Docetaxel or Paclitaxel.
  • the microtubule inhibitor is Docetaxel.
  • the microtubule inhibitor is Paclitaxel.
  • the paclitaxel or docetaxel includes preparations thereof, such as paclitaxel liposomes, albumin-paclitaxel, etc.
  • the microtubule inhibitor is Eribulin.
  • the Eribulin is also called Eribulin/Eribulin, and its CAS number is 253128-41-5.
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody, a PD-1/PD-L1 small molecule inhibitor or a TIGIT inhibitor.
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody.
  • the anti-PD-1/PD-L1 antibody is pembrolizumab or tislelizumab. Tislelizumab, Nivolumab, Toripalimab, Atezolizumab, durvalumab, Avelumab, Camrelizumab, Sintilimab, Cemiplimab, envafolimab, BMS-936559, JS003, SHR-1316, GS- 4224, AN-4005 or MX-10181.
  • the immune checkpoint inhibitor is a small molecule inhibitor of PD-1/PD-L1.
  • the small molecule inhibitor of PD-1/PD-L1 is INCB-086550, lazertinib ( Lazertinib), IMMH-010, CA-170, ABSK043 or RRx-001.
  • the immune checkpoint inhibitor is a TIGIT inhibitor.
  • the TIGIT inhibitor is Ociperlimab (Ociperlimab/BGB-A1217), Vibostolimab (Vibostolimab), domvanalimab (AB154 ), Tiragolumab, Belrestotug, Etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939 , COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.
  • the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof
  • the microtubule inhibitor is Docetaxel
  • the immune checkpoint inhibitor is anti-PD-1/PD- L1 antibodies or PD-1/PD-L1 small molecule inhibitors.
  • the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, and the micron
  • the tube inhibitor is Docetaxel; the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody.
  • the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof
  • the microtubule inhibitor is Paclitaxel
  • the immune checkpoint inhibitor is anti-PD-1/PD-L1 Antibodies or PD-1/PD-L1 small molecule inhibitors.
  • the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof
  • the microtubule inhibitor is Paclitaxel
  • the immune checkpoint inhibitor is anti-PD-1/PD-L1 Antibody.
  • the FAK inhibitor, the microtubule inhibitor and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.
  • the tumor is bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer).
  • melanoma myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma) (like cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, salivary gland cancer, spindle cell carcinoma anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin lymphoma, Hodgkin lymphoma, glioma, or hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (AML), acute
  • the tumor is preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma or pancreatic cancer.
  • the tumor is breast cancer, ovarian cancer or colon cancer (including colorectal cancer).
  • Figure 1 shows staining using Annexin V kit after FAK silencing combined with 0.3 ⁇ M or 1 ⁇ M Docetaxel for 48 hours.
  • Figure 2 shows the enhanced calreticulin release and exposure after FAK silencing combined with 1 ⁇ M Docetaxel for 48 hours.
  • Figure 3 shows FAK silencing combined with 0.15 ⁇ M Eribulin for 48 hours and stained using the Annexin V kit.
  • Figure 4 shows the enhanced calreticulin release and exposure after FAK silencing combined with 0.15 ⁇ M Eribulin for 48 hours.
  • Figure 5 shows the IC50 value of Docetaxel combined with IN10018 in colon cancer cell CT26.
  • Figure 6 shows a white light microscope photo of colon cancer CT26 cells taken after incubation with drugs for 48 hours.
  • Figure 7a shows the percentage of CRT-positive cells after colon cancer CT26 cells were incubated with drugs for 48 hours
  • Figure 7b shows the percentage of Annexin V-positive cells after colon cancer CT26 cells were incubated with drugs for 48 hours.
  • Figure 8a shows the percentage of Calreticulin (CRT) positive cells after mouse breast cancer 4T1 cells were incubated with drugs for 48 hours
  • Figure 8b shows the percentage of Annexin-V positive cells after mouse breast cancer 4T1 cells were incubated with drugs for 48 hours
  • Figure 8c shows The percentage of GRP94-positive cells after mouse breast cancer 4T1 cells were incubated with drugs for 48 hours.
  • Figure 9a shows the percentage of Calreticulin (CRT) positive cells after mouse ovarian epithelial cancer ID8 cells were incubated with drugs for 48 hours
  • Figure 9b shows the percentage of Annexin-V positive cells after mouse ovarian epithelial cancer ID8 cells were incubated with drugs for 48 hours.
  • CRT Calreticulin
  • Figure 10a shows the percentage of Calreticulin (CRT) positive cells after human ovarian epithelial cancer TOV-21G cells were incubated with drugs for 48 hours;
  • Figure 10b shows the percentage of Annexin-V positive cells after human ovarian epithelial cancer TOV-21G cells were incubated with drugs for 48 hours. .
  • Figure 11a shows the percentage of Calreticulin (CRT) positive cells after mouse colon cancer CT26 cells were incubated with Docetaxel and other drugs for 48 hours;
  • Figure 11b shows the percentage of Annexin-V positive cells after mouse colon cancer CT26 cells were incubated with Docetaxel and other drugs for 48 hours. .
  • Figure 12a shows the percentage of Calreticulin (CRT) positive cells after mouse colon cancer CT26 cells were incubated with Eribulin and other drugs for 48 hours
  • Figure 12b shows the percentage of Annexin-V positive cells after mouse colon cancer CT26 cells were incubated with Eribulin and other drugs for 48 hours.
  • Figure 13a shows the percentage of Calreticulin (CRT) positive cells after mouse colon cancer CT26 cells were incubated with Paclitaxel and other drugs for 48 hours
  • Figure 13b shows the percentage of Annexin-V positive cells after mouse colon cancer CT26 cells were incubated with Paclitaxel and other drugs for 48 hours.
  • Figure 14a shows the percentage of Calreticulin (CRT) positive cells after incubation of mouse breast cancer 4T1 cells with Docetaxel and other drugs for 48 hours;
  • Figure 14b shows the percentage of Annexin-V positive cells after incubation of mouse breast cancer 4T1 cells with Docetaxel and other drugs for 48 hours. .
  • Figure 15a shows the percentage of Calreticulin (CRT) positive cells after incubation of mouse breast cancer 4T1 cells with Eribulin and other drugs for 48 hours
  • Figure 15b shows the percentage of Annexin-V positive cells after incubation of mouse breast cancer 4T1 cells with Eribulin and other drugs for 48 hours.
  • Figure 16 shows the changes in tumor volume after administration of different test substances in the subcutaneous allograft tumor model of breast cancer 4T1 cell BALB/c mice.
  • Figure 17 shows the changes in mouse body weight after administration of different test substances in the subcutaneous allograft tumor model of breast cancer 4T1 cell BALB/c mice.
  • Figure 18a shows the percentage of Calreticulin (CRT) positive cells after incubation of mouse breast cancer 4T1 cells with Docetaxel and other drugs for 48 hours
  • Figure 18b shows the percentage of Annexin-V positive cells after incubation of mouse breast cancer 4T1 cells with Docetaxel and other drugs for 48 hours.
  • Figure 19a shows the percentage of Calreticulin (CRT) positive cells after incubation of mouse breast cancer 4T1 cells with Eribulin and other drugs for 48 hours
  • Figure 19b shows the percentage of Annexin-V positive cells after incubation of mouse breast cancer 4T1 cells with Eribulin and other drugs for 48 hours.
  • FAK inhibitor refers to a potent inhibitor of FAK, which may be suitable for mammals, especially humans.
  • the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, and the structure of IN10018 is as follows:
  • the Defactinib is also called defatinib, and its CAS number is 1345713-71-4; the CAS number of GSK2256098 is 1224887-10-8.
  • the CAS number of PF-00562271 is 717907-75-0; the CAS number of VS-4718 is 1061353-68-1; the APG-2449 is developed by Ascentage Pharmaceuticals; the CAS number of AMP945 is 1393653- 34-3.
  • the FAK inhibitor is preferably IN10018, Defactinib or a pharmaceutically acceptable salt thereof.
  • the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, especially IN10018 tartrate.
  • microtubule inhibitor refers to a potent inhibitor of microtubules/tubulin, which may be suitable for mammals, especially humans. Microtubules are components of the cytoskeleton and are found throughout the cytoplasm. tubulin It is one of several members of the small family of globulin. The tubulin superfamily includes 5 different families, ⁇ , ⁇ , ⁇ , ⁇ and ⁇ tubulin. The sixth family only exists in embryonic protozoa of animals and plants. The most common members of the tubulin family are alpha-tubulin and beta-tubulin, which are proteins that make up microtubules.
  • Microtubule inhibitors bind to tubulin to promote or inhibit the assembly of microtubules, interfere with the normal structure and function of the spindle composed of microtubules, interfere with cell mitosis, inhibit cell proliferation, and exert clear anti-tumor effects.
  • Microtubule inhibitors are a large class of chemotherapy drugs, including taxanes, eribulin, ixabepilone, and vinca alkaloids.
  • paclitaxel refers to a large class of chemotherapy drugs, including the drug paclitaxel, which is extracted from natural tree bark, and the synthetic docetaxel.
  • the paclitaxel or docetaxel mentioned in the claims of the present invention includes its preparations, such as paclitaxel liposomes, albumin-paclitaxel, etc.
  • the Eribulin is also called Eribulin/Eribulin, and its CAS number is 253128-41-5.
  • the ixabepilone is also known as Ixabepilone, azaepothilone B or BMS-247550, and its CAS number is 219989-84-1.
  • immune checkpoint inhibitor refers to drugs that can improve the activity of the immune system by regulating immune checkpoint pathways (such as PD-1, TIGIT, CTLA-4, LAG-3, TIM-3, etc.).
  • the immune checkpoint inhibitor is an antagonist of the PD-1/PD-L1 (programmed cell death protein 1) pathway (also known as a "PD-1 inhibitor”) or a TIGIT inhibitor.
  • PD-1 inhibitors are also referred to as PD-1/PD-L1 inhibitors in this disclosure.
  • the PD-1/PD-L1 inhibitor is a PD-1/PD-L1 antibody
  • the PD-1/PD-L1 antibody includes but is not limited to PD-1/PD-L1 Bolizumab (Keytruda/K drug), Tislelizumab (Tislelizumab/Baizian), Nivolumab (Nivolumab), Toripalimab (Toripalimab/Tuoyi), Durvalumab (Infinifer/Durvalumab/durvalumab), Avelumab (Avelumab/Bavencio), Atezolizumab (MPDL3280A/Atezolizumab/Tecentriq/T drug), BMS-936559 (all Human anti-PD-L1 IgG4 monoclonal antibody), GS-4224, AN-4005 or MX-10181.
  • the PD-1 inhibitor is to
  • PD-1/PD-L1 inhibitors also include PD-1/PD-L1 small molecule inhibitors.
  • the PD-1/PD-L1 small molecule inhibitors are INCB-086550, Laziti Lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.
  • TIGIT (also known as WUCAM, Vstm3, VSIG9) is a receptor of the Ig superfamily and is a successor Novel immune checkpoints after PD-1/PD-L1.
  • the PD-1/PD-L1 inhibitor is a TIGIT inhibitor
  • the TIGIT inhibitor includes but is not limited to Ociperlimab/BGB- A1217), Vibostolimab, domvanalimab (AB154), Tiragolumab, Belrestotug, Etigilimab, ONO-4686, JS-006, AZD-2936, HLX -301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207 , HB0036 or IBI-321.
  • TIGIT inhibitors include but is not limited to Ociperlimab/BGB-
  • pharmaceutical combination or “pharmaceutical combination product” may refer to a fixed combination in the form of a dosage unit (for example, all active pharmaceutical ingredients are present in one dosage form) or a kit of products for combined administration. Refers to the combination of a drug and instructions indicating that the drug can be used in combination with one or more other drugs.
  • combination therapy or “combination drug” refers to the combination of one drug with one or more other drugs to treat a disease, including the combination of one drug with another one or more drugs. This also includes the combination of a drug and instructions indicating that the drug can be used in combination with one or more other drugs.
  • “Simultaneous or sequential administration” in this application refers to two or more drugs administered simultaneously or at a certain time interval within one administration cycle (for example, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours). Administered sequentially, the methods of drug administration (such as oral, intravenous, intramuscular or subcutaneous administration, etc.) may be the same or different, and the administration frequency/period of two or more drugs may be the same or different. When the treatment methods, products or uses of the present disclosure involve two drugs, the two drugs can be administered separately at the same time or at certain intervals.
  • the three drugs can be administered at the same time point, or two drugs can be administered at one time point and one drug can be administered at another time point, or all Each of the three drugs was administered at different time points.
  • the PD-1/PD-L1 inhibitor is administered intravenously (eg, as an intravenous infusion) or subcutaneously, or orally.
  • the PD-1/PD-L1 inhibitor is administered as an intravenous infusion.
  • a TIGIT inhibitor is administered intravenously (eg, as an intravenous infusion) or subcutaneously, or orally.
  • the TIGIT inhibitor is administered as an intravenous infusion.
  • immune checkpoint inhibitors to treat cancer depends on the presence of tumor antigen-specific T cells within tumor tissue. This requires that the tumor tissue expresses antibodies that distinguish itself from its non-transformed counterparts. origin, for example, through novel protein products called neoantigens. Tumor neoantigen burden is closely related to immunogenicity and sensitivity (e.g., to checkpoint inhibitor therapies), meaning that less immunogenic tumors should be largely resistant to these agents. Therapies designed to release tumor antigens that can be taken up by APCs, such as those that induce immunogenic cell death (ICD), may promote effective anti-tumor immunity, especially when further combined with checkpoint inhibitors.
  • ICD immunogenic cell death
  • treatment refers to the administration of one or more pharmaceutical substances to a subject suffering from a disease or having symptoms of said disease in order to cure, alleviate, alleviate, alter, treat, ameliorate, ameliorate or affect said disease.
  • Disease or symptoms of said disease In some embodiments, the disease is tumor or cancer.
  • tumor refers to abnormal lesions formed by the body's abnormal growth caused by various tumorigenic factors. Cells in local tissues lose normal control of their growth at the genetic level, resulting in abnormal proliferation of their clonal types.
  • the tumors include, but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer).
  • small cell lung cancer small cell lung cancer
  • melanoma myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including Squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, salivary gland cancer, spindle cell carcinoma Metastases, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin lymphoma, Hodgkin lymphoma, glioma, or hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia Leukemia (ALL), diffuse large B
  • the tumor is preferably breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer; in some embodiments , the tumor is breast cancer, ovarian cancer or colon cancer (including colorectal cancer).
  • the term "subject” or “subject” refers to mammals and non-mammals.
  • Mammal means any member of the class Mammalia, which includes, but is not limited to: humans; non-human primates, such as chimpanzees and other ape and monkey species; farm animals, such as cattle, horses, sheep, goats, and pigs; Domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds.
  • the term "subject” does not identify a specific age or gender. In some embodiments, the subject is a human.
  • pharmaceutically acceptable means nontoxic, biologically tolerable, and suitable for administration to a subject.
  • pharmaceutically acceptable salts refers to nontoxic, biologically tolerable acid addition salts suitable for administration to a subject, including, but not limited to, acid addition salts with inorganic acids. , such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed with organic acids, such as formates, acetates, etc.
  • Acid malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate , benzoate, salicylate, stearate and salts formed with alkanedicarboxylic acids of the formula HOOC-(CH 2 ) n -COOH (where n is 0-4), etc.
  • pharmaceutically acceptable acid addition salts can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds.
  • suitable solvent for preparing acid addition salts from basic compounds.
  • One skilled in the art will be able to identify, without undue experimentation, various synthetic methods that can be used to prepare nontoxic pharmaceutically acceptable acid addition salts.
  • composition means that it must be chemically and/or toxicologically compatible with the other ingredients including the formulation, and/or with the subject to be treated therewith.
  • therapeutically effective amount refers to an amount generally sufficient to produce a beneficial therapeutic effect in a subject. Conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of disease, subject's medical history, subject's health condition, subject degree of response to drugs, etc.) to determine the therapeutically effective dose of the present invention.
  • inhibitor refers to a reduction in the baseline activity of a biological activity or process.
  • kit used in this article refers to a box used to contain chemical reagents for detecting chemical components, drug residues, virus types, etc.
  • the kit of the present invention may include (i) one, two or three of FAK inhibitors, microtubule inhibitors and immune checkpoint inhibitors; and (ii) instructions indicating that FAK can be used inhibitors, microtubule inhibitors, and immune checkpoint inhibitors to treat tumors in subjects.
  • the kit includes (i) a FAK inhibitor; and (ii) instructions indicating that the FAK inhibitor, microtubule inhibitor, and immune checkpoint inhibitor can be used to treat tumors in a subject.
  • the kit includes (i) a microtubule inhibitor; and (ii) instructions indicating that the FAK inhibitor, microtubule inhibitor, and immune checkpoint inhibitor can be used to treat tumors in a subject .
  • the kit includes (i) an immune checkpoint inhibitor; and (ii) instructions indicating that a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor can be used to treat a subject.
  • Tumor In one embodiment, the kit includes (i) FAK inhibitors, microtubule inhibitors, and immune checkpoint inhibitors; and (ii) instructions indicating that FAK inhibitors, microtubule inhibitors, and immune checkpoint inhibitors can be used to treat tumors in a subject .
  • the kit includes (i) a FAK inhibitor; and (ii) instructions indicating that the FAK inhibitor and the microtubule inhibitor can be used to treat tumors in a subject. In one embodiment, the kit includes (i) a microtubule inhibitor; and (ii) instructions indicating that the microtubule inhibitor and the FAK inhibitor can be used to treat tumors in a subject.
  • kits may include a first container including at least one dose of a drug including a FAK inhibitor, a second container including at least one dose of a microtubule inhibitor, a third container and a package insert, The third container includes at least one dose of an immune checkpoint inhibitor drug, and the package insert includes instructions for using the drug to treat the subject's tumor.
  • the first container, the second container, and the third container may contain the same or different shapes (eg, vials, syringes, and bottles) and/or materials (eg, plastic or glass). Kits may also include other materials that may aid in administering the medication, such as diluents, filters, IV bags and tubing, needles, and syringes.
  • FAK inhibitor, microtubule inhibitor, or immune checkpoint inhibitor administered to a subject will depend on various factors, such as a given drug or compound, drug formulation, route of administration, type of disease, condition, The identity of the subject or host being treated, etc., however, can still be determined routinely by those skilled in the art. For example, determining an effective amount also depends on the degree, severity and type of cell proliferation. A technician will be able to determine the appropriate dosage based on these and other factors.
  • FAK inhibitors, microtubule inhibitors, or immune checkpoint inhibitors can be administered in a suitable manner, such as oral, intravenous, intramuscular, or subcutaneous administration.
  • the drug may be administered orally with a pharmaceutically acceptable carrier such as an inert diluent or an absorbable edible carrier. They can be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or can be mixed directly with the patient's food.
  • a pharmaceutically acceptable carrier such as an inert diluent or an absorbable edible carrier. They can be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or can be mixed directly with the patient's food.
  • the drug may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, or wafers. Tablets, lozenges, pills, capsules, etc.
  • a binder such as tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrant such as corn starch, potato starch , alginic acid, etc.
  • lubricants such as magnesium stearate
  • sweeteners such as sucrose, fructose, lactose or aspartame; or flavoring agents.
  • solutions of the drug may be prepared in water, optionally mixed with a nontoxic surfactant.
  • Exemplary pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient suitable for the extemporaneous preparation of sterile injection or infusion solutions or dispersions. Regardless, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage.
  • Sterile injectable solutions can be prepared by incorporating the required amount of the drug in an appropriate solvent with various other ingredients required from above, followed by filtered sterilization.
  • the preferred methods of preparation may be vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient plus any other desired ingredients present after previous sterile filtration.
  • the amount of FAK inhibitor, microtubule inhibitor, or immune checkpoint inhibitor required for treatment may vary not only with the specific agent selected, but also with the route of administration, the nature of the disease being treated, and the age and age of the patient. varies depending on the situation and can ultimately be determined at the discretion of the attending physician or clinician. In general, however, dosages may range from about 0.1 to about 50 mg/kg of body weight per day.
  • the FAK inhibitors are administered at doses ranging from 5 mg/day to 300 mg/day in adults.
  • IN10018, or a pharmaceutically acceptable salt thereof is administered at a dose of 5 mg/day to 100 mg/day in adults.
  • IN10018, or a pharmaceutically acceptable salt thereof is administered in adults. In adults doses of 25 mg/day to 100 mg/day are administered as free base.
  • microtubule inhibitors are administered in a dose range of 20-60 mg/ m per week in adults.
  • docetaxel is administered at a dose of 20-25 mg/ m per week in adults;
  • paclitaxel or a formulation thereof is administered at a dose of 45-60 mg/ m per week in adults.
  • the dosage is based on paclitaxel;
  • Eribulin is administered at 1.4 mg/m 2 intravenously over 2 to 5 minutes on the 1st and 8th days of the 21-day treatment course.
  • the immune checkpoint inhibitor is administered at a dose of 2-10 mg/kg or 50-1200 mg in adults every 2 to 3 weeks. In a specific embodiment, the immune checkpoint inhibitor is administered at a dose of 3-10 mg/kg or 100-1200 mg in adults, once every 2 weeks to 3 weeks.
  • the present disclosure also discloses the following:
  • FAK inhibitors for use in methods of treating tumors in a subject.
  • the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof, further preferably IN10018 or a pharmaceutically acceptable salt thereof, Especially IN10018 tartrate, the structure of IN10018 is as follows:
  • microtubule inhibitor is a taxane, eribulin, ixapi Ixempra or vinca alkaloids.
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody
  • the anti-PD-1/PD-L1 antibodies are pembrolizumab, Tislelizumab, Nivolumab, Toripalimab, Attilide Atezolizumab, durvalumab, Avelumab, Camrelizumab, Sintilimab, Cemiplimab ), envolimab (envafolimab), BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.
  • the immune checkpoint inhibitor is a PD-1/PD-L1 small molecule inhibitor
  • the PD-1/PD-L1 small molecule inhibitor is INCB-086550, Lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.
  • the immune checkpoint inhibitor is a TIGIT inhibitor
  • the TIGIT inhibitor for Ociperlimab (Ociperlimab/BGB-A1217), Vibostolimab (Vibostolimab), domvanalimab (AB154), Tiragolumab (Tiragolumab), Belrestotug, Etigilimab (Etigilimab), ONO -4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005 , ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.
  • the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof
  • the microtubule inhibitor is taxane Alcohol (Paclitaxel)
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody or a PD-1/PD-L1 small molecule inhibitor, especially the FAK inhibitor is IN10018 or its pharmaceutically acceptable salt, the microtubule inhibitor is Paclitaxel; the immune checkpoint inhibitor is anti-PD-1/PD-L1 antibody.
  • the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 1-14, the FAK inhibitor, the microtubule inhibitor and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.
  • the tumor is bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer) cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma , pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, smooth muscle Sarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland carcinoma, metasta
  • kits or pharmaceutically acceptable composition comprising:
  • kits or composition of embodiment 18, wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or pharmaceutically acceptable ones thereof
  • the salt is preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof, and further preferably IN10018 or a pharmaceutically acceptable salt thereof, especially IN10018 tartrate.
  • the structure of IN10018 is as follows:
  • kits or composition of embodiments 18-19, wherein the microtubule inhibitor is a taxane, Eribulin, Ixempra or a vinca alkaloid .
  • kit or composition of any one of embodiments 20-21, wherein the taxane is Docetaxel, Paclitaxel, Cabazitaxel or Cephalomannine is preferably Docetaxel or Paclitaxel.
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody
  • the anti-PD-1/PD -L1 antibodies are pembrolizumab, Tislelizumab, Nivolumab, Toripalimab, Atezolizumab , durvalumab, Avelumab, Camrelizumab, Sintilimab, Cemiplimab, Envolimab Anti-(envafolimab), BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.
  • the immune checkpoint inhibitor is a small molecule inhibitor of PD-1/PD-L1, further, the PD-1/PD -L1 small molecule inhibitors are INCB-086550, Lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.
  • TIGIT inhibitor is Ociperlimab /BGB-A1217), Vibostolimab, domvanalimab (AB154), Tiragolumab, Belrestotug, Etigilimab, ONO-4686,
  • the agent is Docetaxel; the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody.
  • kits or composition of embodiment 33, wherein the tumor is breast cancer, ovarian cancer, or colon cancer (including colorectal cancer).
  • a method of treating a tumor in a subject comprising administering to the subject a therapeutically effective amount of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor.
  • microtubule inhibitor is a taxane, Eribulin, Ixempra or a vinca alkaloid.
  • microtubule inhibitor is Docetaxel
  • microtubule inhibitor is Paclitaxel
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody
  • the anti-PD-1/PD-L1 antibody is Pembrolizumab, Tislelizumab, Nivolumab, Toripalimab, Atezolizumab, Duvalumab Anti-durvalumab, Avelumab, Camrelizumab, Sintilimab, Cemiplimab, envafolimab , BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.
  • the immune checkpoint inhibitor is a PD-1/PD-L1 small molecule inhibitor, further, the PD-1/PD-L1 small molecule
  • the inhibitors are INCB-086550, Lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.
  • the immune checkpoint inhibitor is a TIGIT inhibitor
  • the TIGIT inhibitor is Ociperlimab/BGB-A1217 ), Vibostolimab, domvanalimab (AB154), Tiragolumab, Belrestotug, Etigilimab, ONO-4686, JS-006, AZD-2936, HLX- 301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.
  • the microtubule inhibitor is Docetaxel
  • the immune checkpoint inhibitor It is an anti-PD-1/PD-L1 antibody or a small molecule inhibitor of PD-1/PD-L1, especially the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, and the microtubule inhibitor is docetaxel.
  • Docetaxel; the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody.
  • the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof
  • the microtubule inhibitor is Paclitaxel
  • the immune checkpoint inhibitor is Anti-PD-1/PD-L1 antibody or PD-1/PD-L1 small molecule inhibitor, especially the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, and the microtubule inhibitor is paclitaxel (Paclitaxel);
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody.
  • the tumor is bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer Cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma , Sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, Ovarian cancer, salivary gland cancer, metastases caused by spindle cell carcinoma, anaplastic
  • FAK inhibitors for use in methods of treating tumors by increasing immunogenic cell death in a subject.
  • the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor of embodiment 52 wherein the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945 , AMP886 or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof, further preferably IN10018 or a pharmaceutically acceptable salt thereof, especially IN10018 tartrate, the IN10018
  • the structure is as follows:
  • the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 54-55, wherein the taxane drug is Docetaxel, Paclitaxel ), cabazitaxel or cephalomannine, preferably docetaxel or paclitaxel.
  • FAK inhibitor, microtubule inhibitor and immunoassay as described in any one of embodiments 52-56 Check the inhibitor, wherein the microtubule inhibitor is Docetaxel.
  • the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52-59, wherein the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody, PD- 1/PD-L1 small molecule inhibitor or TIGIT inhibitor.
  • the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52-60, wherein the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody, further , the anti-PD-1/PD-L1 antibodies are pembrolizumab, Tislelizumab, Nivolumab, Toripalimab, Atezolizumab, durvalumab, Avelumab, Camrelizumab, Sintilimab, cimeprimab Anti-(Cemiplimab), envolimab (envafolimab), BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody
  • the anti-PD-1/PD-L1 antibodies are pembrolizumab, Tislelizumab, Nivolumab, Toripalimab, Atezolizumab, durvaluma
  • the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor as described in any one of embodiments 52-60, wherein the immune checkpoint inhibitor is a PD-1/PD-L1 small molecule inhibitor, further , the PD-1/PD-L1 small molecule inhibitor is INCB-086550, Lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.
  • the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52-60, wherein the immune checkpoint inhibitor is a TIGIT inhibitor, further, the TIGIT inhibitor For Ociperlimab (Ociperlimab/BGB-A1217), Vibostolimab (Vibostolimab), domvanalimab (AB154), Tiragolumab (Tiragolumab), Belrestotug, Etigilimab (Etigilimab), ONO -4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005 , ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.
  • Ociperlimab Ociperlimab/BGB-A1217)
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody Or PD-1/PD-L1 small molecule inhibitor, especially the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, and the microtubule inhibitor is Docetaxel;
  • the immune test Point inhibitors are anti-PD-1/PD-L1 antibodies.
  • the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor of embodiment 52 wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, and the microtubule inhibitor is taxane Alcohol (Paclitaxel); the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody or a PD-1/PD-L1 small molecule inhibitor, especially the FAK inhibitor is IN10018 or its pharmaceutically acceptable salt, the microtubule inhibitor is Paclitaxel; the immune checkpoint inhibitor is anti-PD-1/PD-L1 antibody.
  • the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof
  • the microtubule inhibitor is taxane Alcohol (Paclitaxel)
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody or a PD-1/PD-L1 small molecule inhibitor, especially the FAK inhibitor is IN10018 or its pharmaceutically acceptable salt, the microtubule inhibitor is Paclitaxel; the immune checkpoint inhibitor is anti-PD-1/PD-L1 antibody.
  • the FAK inhibitor, microtubule inhibitor and immune checkpoint inhibitor according to any one of embodiments 52-65, the FAK inhibitor, the microtubule inhibitor and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.
  • the tumor is bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer) cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma , pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, smooth muscle Sarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland carcinoma,
  • a method of treating tumors by increasing immunogenic cell death in a subject comprises administering to said subject a therapeutically effective amount of a FAK inhibitor, a microtubule inhibitor, and an immune checkpoint inhibitor.
  • the FAK inhibitor is IN10018, Defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof, further preferably IN10018 or Its pharmaceutically acceptable salts, especially IN10018 tartrate, the structure of IN10018 is as follows:
  • microtubule inhibitor is a taxane, Eribulin, Ixempra, or a vinca alkaloid.
  • microtubule inhibitor is a taxane
  • Taxane is Docetaxel, Paclitaxel, Cabazitaxel or cephalomannine (Cephalomannine), preferably docetaxel (Docetaxel) or paclitaxel (Paclitaxel).
  • microtubule inhibitor is Docetaxel.
  • microtubule inhibitor is Paclitaxel
  • microtubule inhibitor is Eribulin.
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody, a PD-1/PD-L1 small molecule inhibitor, or a TIGIT inhibitor .
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody
  • the anti-PD-1/PD-L1 antibody is Pembrolizumab, Tislelizumab, Nivolumab, Toripalimab, Atezolizumab, Duvalumab Anti-durvalumab, Avelumab, Camrelizumab, Sintilimab, Cemiplimab, envafolimab , BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.
  • the immune checkpoint inhibitor is a PD-1/PD-L1 small molecule inhibitor, further, the PD-1/PD-L1 small molecule
  • the inhibitors are INCB-086550, Lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.
  • the immune checkpoint inhibitor is a TIGIT inhibitor
  • the TIGIT inhibitor is Ociperlimab/BGB-A1217 ), Vibostolimab, domvanalimab (AB154), Tiragolumab, Belrestotug, Etigilimab, ONO-4686, JS-006, AZD-2936, HLX- 301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.
  • the microtubule inhibitor is Docetaxel
  • the immune checkpoint inhibitor It is an anti-PD-1/PD-L1 antibody, a small molecule inhibitor of PD-1/PD-L1, especially the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, and the microtubule inhibitor is docetaxel.
  • Docetaxel; the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody.
  • the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof
  • the microtubule inhibitor is Paclitaxel
  • the immune checkpoint inhibitor is Anti-PD-1/PD-L1 antibody or PD-1/PD-L1 small molecule inhibitor, especially, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, and the microtubule inhibitor is taxane Paclitaxel
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody.
  • the tumor is bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer Cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma , Sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, Ovarian cancer, salivary gland cancer, metastases from spindle cell carcinoma, ana
  • FAK inhibitor for the preparation of a medicament for treating a tumor in a subject, wherein the FAK inhibitor, microtubule inhibitor, and immune checkpoint inhibitor are administered to the subject.
  • microtubule inhibitor for the preparation of a medicament for treating a tumor in a subject, wherein a FAK inhibitor, the microtubule inhibitor and an immune checkpoint inhibitor are administered to the subject.
  • an immune checkpoint inhibitor for the preparation of a medicament for treating a tumor in a subject, wherein a FAK inhibitor, a microtubule inhibitor, and the immune checkpoint inhibitor are administered to the subject.
  • FAK inhibitors in the preparation of drugs for use in combination with microtubule inhibitors and immune checkpoint inhibitors to treat tumors.
  • microtubule inhibitors in the preparation of drugs for combination with FAK inhibitors and immune checkpoint inhibitors to treat tumors.
  • microtubule inhibitor in the preparation of a medicament for the treatment of tumors in combination with a FAK inhibitor and an immune checkpoint inhibitor.
  • microtubule inhibitor is a taxane, Eribulin, Ixempra or a vinca alkaloid.
  • microtubule inhibitor is a taxane
  • microtubule inhibitor is Docetaxel
  • microtubule inhibitor is Paclitaxel
  • microtubule inhibitor is Eribulin.
  • the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody
  • the anti-PD-1/PD-L1 antibody is Pembrolizumab, Tislelizumab, Nivolumab, Toripalimab, Atezolizumab, Duvalumab Anti-durvalumab, Avelumab, Camrelizumab, Sintilimab, Cemiplimab, envafolimab , BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.
  • PD-1/PD-L1 small molecule inhibitors are INCB-086550, Lazertinib, IMMH-010, CA-170, ABSK043 Or RRx-001.
  • the immune checkpoint inhibitor is a TIGIT inhibitor
  • the TIGIT inhibitor is Ociperlimab/BGB-A1217 ), Vibostolimab, domvanalimab (AB154), Tiragolumab, Belrestotug, Etigilimab, ONO-4686, JS-006, AZD-2936, HLX- 301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.
  • the agent is Paclitaxel; the immune checkpoint inhibitor is an anti-PD-1/PD-L1 antibody.
  • any one of embodiments 98-109, the FAK inhibitor, the microtubule inhibitor, and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.
  • the tumor is bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer Cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma , Sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, Ovarian cancer, salivary gland cancer, metastases from spindle cell carcinoma, ana
  • the tumor is breast cancer , ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma or pancreatic cancer.
  • Example 1 Study on FAK target inhibition to enhance immunogenic cell death of ovarian cancer cells against Docetaxel
  • Experimental Antibody Recombinant Alexa 647 fluorescent Anti-Calreticulin (anti-calreticulin) antibody (Abcam, ab196159), Annexin V apoptosis detection kit (Invitrogen, A35110).
  • FAK siRNA is provided by Jima Gene, and the sequence is shown in the table below:
  • SK-OV-3 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM respectively. 24 hours after transfection, 0.3 ⁇ M or 1 ⁇ M Docetaxel was treated for 48 hours respectively, and the cells were stained using Annexin V kit and detected using flow cytometry. The apoptosis values were statistically compared with the control group and plotted using Graphpad 8.0. The results showed that compared with the control group, apoptosis was significantly enhanced after Docetaxel treatment in the FAK silencing group, as shown in Figure 1.
  • SK-OV-3 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM respectively. 24 hours after transfection, 1 ⁇ M Docetaxel was treated for 48 hours, fluorescent staining was performed with Calreticulin antibody, and the staining results were analyzed by flow cytometry. FlowJo software results statistics show that after FAK silencing combined with Docetaxel, the release and exposure of Calreticulin were significantly enhanced, as shown in Figure 2.
  • FAK siRNA is provided by Jima Gene, and the sequence is shown in the table below:
  • MDA-MB-231 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM respectively. 24 hours after transfection, 0.15 ⁇ M Eribulin was treated for 48 hours, and the cells were stained using Annexin V kit and detected using flow cytometry. The early and late cell apoptosis values were counted and compared with the DMSO control group and plotted using Graphpad 8.0. The results showed that compared with the control group, early and late apoptosis in the FAK silencing group was significantly enhanced after Eribulin treatment, as shown in Figure 3.
  • MDA-MB-231 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM respectively. 24 hours after transfection, 0.15 ⁇ M Eribulin was treated for 48 hours, fluorescent staining was performed with Calreticulin antibody, and the staining results were analyzed by flow cytometry. FlowJo software result statistics show that after FAK silencing combined with Eribulin, the release and exposure of Calreticulin were significantly enhanced, as shown in Figure 4.
  • CT26 was cultured with RPMI-1640 (Shanghai Yuanpei, classification number: L210KJ, batch number: F210916) + 10% FBS (Gibco, classification number: 10099-141c, batch number: 2158737cp), and passaged twice.
  • RPMI-1640 Sudhai Yuanpei, classification number: L210KJ, batch number: F210916) + 10% FBS (Gibco, classification number: 10099-141c, batch number: 2158737cp)
  • the first concentration is 30 ⁇ M, 3-fold dilution, the last one is the control, the drug concentration is 0, and each drug concentration is set to 3 composite wells.
  • another group of cells was established using the same drug concentration as described above. The difference is that 5 ⁇ M IN10018 is added to each well, the drugs are mixed, and incubated at 37°C in a 5% CO2 incubator for 72 hours.
  • CT26 cells Institute of Cell Science, Chinese Academy of Sciences
  • RPMI-1640 Shanghai Yuanpei, classification number: L210KJ, batch number: F210916) + 10% FBS (Gibco, classification number: 10099-141c, batch number: 2158737cp)
  • FBS FBS
  • the first group was the control group and culture medium was added.
  • the second group was IN10018 with a concentration of 5 ⁇ M.
  • the third group was Docetaxel (MCE, classification number: HY-B0011, batch number: 111613). , the concentration is 0.1 ⁇ M
  • the fourth group is the combination group of IN10018 (5 ⁇ M) and Docetaxel (0.1 ⁇ M). Mix the drugs and incubate in a 5% CO2 incubator at 37°C for 48 hours.
  • Apoptosis detection kit (Beyotime, catalog number: CL062L, batch number: 021921210811), add 195 ⁇ l Annexin-V-FITC conjugate, mix the cells gently, add 5 ⁇ l Annexin-V-FITC antibody, mix gently , add 10 ⁇ l PI dye to mix, incubate at room temperature for 15 minutes in the dark, and then analyze on a flow cytometer.
  • Example 5 Study on the induction of immunogenic cell death targets by Eribulin and IN10018 in mouse breast cancer 4T1 cells
  • 4T1 cells were cultured in monolayer in vitro.
  • the culture conditions were: RPMI-1640 medium plus 10% fetal bovine serum, 37°C, 5% CO 2 .
  • the cells are in the exponential growth phase and the adhesion confluence reaches 80%-90%, the cells are harvested and plated.
  • 4T1 cells were digested with trypsin and collected and counted. Based on the counting results, the cells were diluted with RPMI-1640+10% FBS to a dilution concentration of 50,000 cells per ml, and then plated on a 12-well cell culture plate. Plate 2 ml of cell suspension per well, which is 100,000 cells. After plating, the cells were cultured in a 37°C, 5% CO2 incubator.
  • the cells were photographed using a microscope, and then the cells were trypsinized and collected for flow cytometry staining.
  • Example 6 Study on the induction of immunogenic cell death targets by Eribulin and IN10018 in mouse ovarian epithelial cancer ID8 cells and human ovarian epithelial cancer TOV-21G cells in vitro
  • ID8 cells and TOV-21G cells are cultured in monolayer in vitro.
  • the culture conditions of ID8 cells are DMEM medium plus 10% fetal bovine serum
  • the culture conditions of TOV-21G cells are RPMI-1640 medium plus 10% fetal bovine serum. All were cultured in a 37°C, 5% CO2 incubator. Perform routine digestion pass-through with trypsin two to three times a week. When the cells are in the exponential growth phase and the adhesion confluence reaches 80%-90%, the cells are harvested and plated.
  • ID8 cells and TOV-21G cells are digested with trypsin, collected and counted. According to the counting results, the cells are diluted with the corresponding complete culture medium to a dilution concentration of 50,000 cells per ml, and then placed on a 12-well cell culture plate. Plate, spread 2ml of cell suspension per well, which is 100,000 cells.
  • the cells were cultured in a 37°C, 5% CO2 incubator.
  • the cells were photographed using a microscope, and then the cells were trypsinized and collected for flow cytometry staining.
  • Example 7 Study on the induction of immunogenic cell death targets in mouse colon cancer CT26 cells by Docetaxel/Eribulin/Paclitaxel and Defactinib in vitro
  • CT26 cells were cultured in monolayer in vitro.
  • the cell culture conditions were: RPMI-1640 medium plus 10% fetal bovine serum, 37°C, 5% CO 2 . Perform routine digestion pass-through with trypsin two to three times a week. When the cells are in the exponential growth phase and the adhesion confluence reaches 80%-90%, the cells are harvested and plated.
  • CT26 cells were digested with trypsin and collected and counted. According to the counting results, the cells were diluted with the corresponding complete culture medium to a dilution concentration of 50,000 cells per ml, and then plated on a 12-well cell culture plate. Each well was plated. 2ml of cell suspension equals 100,000 cells.
  • the cells were cultured in a 37°C, 5% CO2 incubator.
  • the cells were photographed using a microscope, and then the cells were digested with trypsin and collected for flow cytometry staining.
  • This experiment evaluated the effect of Docetaxel/Eribulin/Paclitaxel alone and in combination with Defactinib on inducing the expression of immune cell death targets in CT26 cells under in vitro conditions.
  • Example 8 Study on the induction of immunogenic cell death targets in mouse breast cancer 4T1 cells by Docetaxel/Eribulin and Defactinib in vitro
  • the compound information is shown in Table 5 (without Paclitaxel), and the main experimental reagent information is shown in Table 2.
  • 4T1 cells were cultured in monolayer in vitro.
  • the cell culture conditions were RPMI-1640 medium plus 10% fetal calf serum and cultured in a 37°C, 5% CO2 incubator. Perform routine digestion pass-through with trypsin two to three times a week. When the cells are in the exponential growth phase and the adhesion confluence reaches 80%-90%, the cells are harvested and plated.
  • 4T1 cells were digested with trypsin and collected and counted. According to the counting results, the cells were diluted with the corresponding complete culture medium to a dilution concentration of 50,000 cells per ml, and then plated on a 12-well cell culture plate. Each well was plated. 2ml of cell suspension equals 100,000 cells.
  • the cells were cultured in a 37°C, 5% CO2 incubator.
  • the cells were photographed using a microscope, and then the cells were trypsinized and collected for flow cytometry staining.
  • Example 9 Study on the in vivo anti-tumor efficacy of docetaxel injection (Docetaxel) in breast cancer 4T1 cell BALB/c mouse subcutaneous allograft tumor model
  • mice Female BALB/c mice aged 6-8 weeks were purchased from Shanghai Slack Experimental Animal Co., Ltd. The experiment began after the animals arrived and were acclimated to the experimental environment. Animals were kept in IVC (independent ventilation system) cages (5 animals per cage) in SPF-level animal rooms. All cages, bedding and drinking water must be sterilized before use. All experimenters should wear protective clothing and latex gloves when operating in the animal room. Cages, feed and drinking water are changed twice a week. The feeding environment and lighting conditions are as follows:
  • Light cycle 12 hours of light, 12 hours of no light
  • Cage Made of polycarbonate, volume 300mm ⁇ 180mm ⁇ 150mm.
  • the bedding material is corn cobs and is changed twice a week.
  • Drinking water Experimental animals can drink sterilized water freely.
  • the animal information card of each cage should indicate the number, gender, strain, and date of receipt of animals in the cage. period, dosing regimen, trial number, group and trial start date.
  • Animal identification Experimental animals are identified with ear tags.
  • Administration volume Based on the mouse body weight of 10 mL/kg, if the body weight drops by more than 15%, the animal will stop administration; wait until the body weight recovers to a 10% decrease before resuming administration.
  • the animal's health condition continues to deteriorate, or the tumor volume exceeds 3000mm 3 , or it has severe disease or pain, it must be euthanized. If the following conditions occur, the veterinarian will be notified and euthanasia will be implemented: obvious weight loss, weight loss of more than 20%; unable to freely eat and drink; the average tumor volume in the control group reaches 2000mm 3 , and the experiment will be terminated.
  • the animals showed the following clinical manifestations and continued to worsen: piloerection, arched back, white ears, nose, eyes or feet, rapid breathing, convulsions, continuous diarrhea, dehydration, slow movement and vocalization.
  • Tumor diameter was measured with vernier calipers three times a week.
  • TGI (%) [1-(Average tumor volume of a certain administration group-Average tumor volume of the administration group at the beginning of treatment)/(Average tumor volume of the solvent control group-Average tumor volume of the solvent control group at the beginning of treatment)] ⁇ 100%.
  • the tumor volume in the control group was 2129.2 ⁇ 322.0mm 3 .
  • the tumor volumes of each treatment group were 1818.7 ⁇ 644.0mm 3 , 2205.7 ⁇ 912.7mm 3 , 1182.9 ⁇ 264.3mm 3 , 1480.3 ⁇ 345.6mm 3 and 829.4 ⁇ 249.1mm 3 respectively. See Table 11 for details.
  • the comprehensive tumor volume was compared with the DTX+IN10018+MAX10181 (10+25+120mg/kg) three-drug combination group, and statistical analysis was performed.
  • the tumor volumes of each dose group at different time periods are shown in Figure 16.
  • Table 11 Data on day 21 after dosing based on grouping
  • the experiment was conducted in accordance with the dosage regimen. During the experiment, the animals were observed for eating, drinking and other activities every day, and the animal weight was recorded three times a week. The animal weight curve is shown in Figure 17. During the entire dosing cycle, animals in the MAX10181-related groups experienced diarrhea, which resulted in the death of one animal each in G3 MAX10181 (120mg/kg) and G5DTX+MAX10181 (10+120mg/kg). In addition, the body weight of DTX+IN10018+MAX10181 (10+25+120mg/kg) decreased, but not more than 10%; the animals in each group were in good mental and motor status, and were relatively tolerant to various administration methods.
  • DTX (10mg/kg), DTX+IN10018 (10+25mg/kg), Both the DTX+MAX10181 (10+120mg/kg) and DTX+IN10018+MAX10181 (10+25+120mg/kg) treatment groups had significant tumor growth inhibition effects, and were statistically different from the control group.
  • the tumor volume of the DTX+IN10018 (10+25mg/kg) group was smaller than that of the DTX (10mg/kg) single drug group, showing that the combination of DTX and IN10018 has better efficacy than the single drug alone.
  • the tumor volume of the DTX+IN10018+MAX10181 (10+25+120mg/kg) three-drug combination group was compared with that of each single-drug group and each two-drug combination group, and was statistically different from the other groups. , showing that the combination of DTX, IN10018 and MAX10181 has a better effect on inhibiting tumor growth.
  • MAX10181 related groups will cause diarrhea in the animals, and at the same time lead to the death of one animal in each of the MAX10181 (120mg/kg) and DTX+MAX10181 (10+120mg/kg) groups, the mental and motor status of the remaining animals Good, indicating that animals show a certain tolerance to the combination of DTX+IN10018+MAX10181 (10+25+120mg/kg).
  • Example 10 Study on the induction of immunogenic cell death target in mouse breast cancer 4T1 cells by docetaxel injection (Docetaxel) and AMP945 in vitro
  • AMP945 is provided by MCE, Lot No.:143253
  • 4T1 cells (from Nanjing Kebai Biotechnology Co., Ltd., Cat. No.: CBP60352) were grown with RPMI-1640 (Shanghai Yuanpei, Cat No.: L210KJ, Lot No.: F210916) + 10% FBS (Gibco, Cat No.: 10099- 141c, Lot No.: 2158737cp), and the culture conditions were 37°C and 5% CO 2 . Perform routine digestion pass-through with trypsin two to three times a week. When the cells are in the exponential growth phase and the adhesion confluence reaches 80%-90%, the cells are harvested and plated. 4T1 cells were digested with trypsin and collected and counted.
  • the cells were diluted with RPMI-1640+10% FBS to a dilution concentration of 50,000 cells per ml, and then plated on a 12-well cell culture plate. Plate 2 ml of cell suspension per well, which is 100,000 cells. After plating, the cells were cultured in a 37°C, 5% CO2 incubator. After the cells were spread for 24 hours, six groups were set up. The first group was the control group and culture medium was added. The second group was AMP945 at a concentration of 3 ⁇ M. The third group was AMP945 at a concentration of 6 ⁇ M. The fourth group was docetaxel injection.
  • the concentration is 0.3 ⁇ M
  • the fifth group is the combination of AMP945 (3 ⁇ M) and Docetaxel (0.3 ⁇ M)
  • the sixth group is the combination of AMP945 (6 ⁇ M) and Docetaxel (0.3 ⁇ M).
  • Example 11 Study on the induction of immunogenic cell death target in mouse breast cancer 4T1 cells by Eribulin and AMP945 in vitro
  • AMP945 is provided by MCE, Lot No.:143253
  • 4T1 cells (from Nanjing Kebai Biotechnology Co., Ltd., Cat. No.: CBP60352) were grown with RPMI1640 (Shanghai Yuanpei, Cat No.: L210KJ, Lot No.: F210916) + 10% FBS (Gibco, Cat No.: 10099-141c, Lot No.: 2158737cp), the culture conditions were 37°C and 5% CO 2 . Perform routine digestion pass-through with trypsin two to three times a week. When the cells are in the exponential growth phase and the adhesion confluence reaches 80%-90%, the cells are harvested and plated. 4T1 cells were digested with trypsin and collected and counted.
  • the cells were diluted with RPMI-1640+10% FBS to a dilution concentration of 50,000 cells per ml, and then plated on a 12-well cell culture plate. Plate 2 ml of cell suspension per well, which is 100,000 cells. After plating, the cells were cultured in a 37°C, 5% CO2 incubator. After the cells were spread for 24 hours, six groups were set up. The first group was the control group and culture medium was added. The second group was AMP945 with a concentration of 3 ⁇ M. The third group was AMP945 with a concentration of 6 ⁇ M. The fourth group was Eribulin with a concentration of 0.3.
  • the fifth group is the combination of AMP945 (3 ⁇ M) and Eribulin (0.3 ⁇ M)
  • the sixth group is the combination of AMP945 (6 ⁇ M) and Eribulin (0.3 ⁇ M). Mix the drugs and incubate at 37°C in a 5% CO2 incubator for 48 hours.

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Abstract

FAK抑制剂、微管抑制剂和免疫检查点抑制剂的组合物、其组成的试剂盒以及其在制备治疗肿瘤药物中的用途。

Description

FAK抑制剂及微管抑制剂的药物组合及用途
本申请要求于2022年8月24日递交的中国专利申请202211018821.9、于2022年9月23日递交的中国专利申请202211165722.3和于2023年7月28日递交的中国专利申请202310940775.6的优先权，在此全文引用上述中国专利申请公开的内容以作为本申请的一部分。
技术领域
本发明属于药物化学领域。具体地，本发明涉及粘着斑激酶(Focal Adhesion Kinase,FAK)抑制剂与其它药物联用治疗肿瘤。
背景技术
肿瘤是威胁人们健康的第二大杀手。免疫原性细胞死亡(Immunogenic cell death，ICD)是基于细胞程序性死亡的叠加效应。癌细胞接触化疗或者靶向治疗类药物的同时可能激活细胞内部的压力信号，这一类压力信号包含内质网压力(ER stress)和活性氧压力(oxidative stress)。在压力信号的作用下细胞会先尝试修复压力，如果压力造成的损伤超出了修复的能力，细胞会启动程序性死亡过程。在这个过程中往往伴随着一类叫做损伤相关分子(Damage associated molecular patterns，DAMPs)的释放，这些分子包括钙网蛋白(calrectulin)，膜联蛋白A1(annexin A1)、HMGB1等。这类DAMPs会特异性的被机体内抗原呈递细胞(Antigen-presenting cells，APC)上的模式识别受体识别，诱导APC成熟、分化和激活，并逐级呈递给效应T细胞等免疫细胞，从而使免疫细胞产生抗原记忆，再次发现相同来源的肿瘤细胞时免疫细胞就会特异性识别并杀伤肿瘤细胞。ICD启动的新的针对肿瘤的特异性免疫反应可增加对免疫检查点抑制剂(Immuno-check point inhibitor，ICI)的敏感，以此增效免疫检查点类抑制剂的作用，并可产生具有免疫记忆持久的抗肿瘤的反应。
FAK，又称为蛋白酪氨酸激酶2(PTK2)，是一种非受体酪氨酸激酶，并且是粘着斑复合体的关键组分。FAK在介导整合素和生长因子信号以调节肿瘤细胞的侵袭、增殖和存活方面发挥着重要作用。
微管是一种动态的细丝状细胞骨架蛋白，也是中心粒的主体分子，微管 纤维有序的动态变化是细胞有丝分裂的重要保证。微管抑制剂与微管蛋白结合促进或抑制微管的装配、干扰微管组成纺锤体的正常结构与功能，具有干扰细胞有丝分裂、抑制细胞增殖的作用，发挥明确的抗肿瘤效应。靶向微管的抗肿瘤药物已成为当今抗肿瘤药物研究的重要方面，目前已经上市的微管抑制剂很多，其中就有紫杉类和艾瑞布林(Eribulin)。紫衫类药物有从天然树皮提取的药物称为紫杉醇，也有合成的多西他赛，现在还有白蛋白紫杉醇等。紫衫类药物为M期周期特异性药物，促进小管聚合成稳定的微管并抑制其聚解，从而使小管的数量显著减少，并可破坏微管网状结构。艾瑞布林(Eribulin)是一种合成的大田软海绵素(halichondrin B)类似物，通过抑制微管解聚，进而导致细胞周期G2/M阻断破坏有丝分裂纺锤体，最终导致细胞调亡。紫杉类和艾瑞布林均为临床常用的化疗药物。但是均会在服用一段时间后产生一定的耐药。
因此，仍然需要找到一种方法去提高化疗中单药的疗效，并进一步克服耐药问题。
发明内容
本公开一方面提供了FAK抑制剂、微管抑制剂和免疫检查点抑制剂在制备用于在对象中治疗肿瘤的药物中的用途。
本公开又一方面提供了FAK抑制剂、微管抑制剂和免疫检查点抑制剂的药物组合产品，其用于在对象中治疗肿瘤。
本公开又一方面提供了一种治疗肿瘤的方法，该方法包括向有需要的对象施用治疗有效量的FAK抑制剂、微管抑制剂和免疫检查点抑制剂。
本公开又一方面提供了一种试剂盒或药学上可接受的组合物，其包括：(a)FAK抑制剂；(b)微管抑制剂；和(c)免疫检查点抑制剂。
本公开又一方面提供了FAK抑制剂和微管抑制剂在制备用于在治疗肿瘤的药物中的用途，其中所述FAK抑制剂用于增强所述微管抑制剂诱导的免疫原性细胞死亡。
本公开又一方面提供了FAK抑制剂，其在治疗肿瘤中用于增强微管抑制剂诱导的免疫原性细胞死亡。
本公开又一方面提供了一种治疗肿瘤的方法，该方法包括向有需要的对象施用治疗有效量的FAK抑制剂和微管抑制剂，其中所述FAK抑制剂用于 增强所述微管抑制剂诱导的免疫原性细胞死亡。
本公开又一方面提供了FAK抑制剂、微管抑制剂和免疫检查点抑制剂在制备用于联合治疗肿瘤的药物中的用途。
本公开又一方面提供了FAK抑制剂在制备用于与微管抑制剂和免疫检查点抑制剂治疗肿瘤的联用药物中的用途。
本公开又一方面提供了微管抑制剂在制备用于与FAK抑制剂和免疫检查点抑制剂治疗肿瘤的联用药物中的用途。
本公开又一方面提供了免疫检查点抑制剂在制备用于与FAK抑制剂和微管抑制剂治疗肿瘤的联用药物中的用途。
本公开又一方面提供了FAK抑制剂在制备用于与微管抑制剂和免疫检查点抑制剂联合治疗肿瘤的药物中的用途。
本公开又一方面提供了微管抑制剂在制备用于与FAK抑制剂和免疫检查点抑制剂联合治疗肿瘤的药物中的用途。
本公开又一方面提供了免疫检查点抑制剂在制备用于与FAK抑制剂和微管抑制剂联合治疗肿瘤的药物中的用途。
本公开又一方面提供了一种试剂盒，其包括：FAK抑制剂；和说明书，该说明书指出该FAK抑制剂可用于与微管抑制剂和免疫检查点抑制剂联合治疗肿瘤。
本公开又一方面提供了一种试剂盒，其包括：微管抑制剂；和说明书，该说明书指出该微管抑制剂可用于与FAK抑制剂和免疫检查点抑制剂联合治疗肿瘤。
本公开又一方面提供了一种试剂盒，其包括：免疫检查点抑制剂；和说明书，该说明书指出该免疫检查点抑制剂可用于与FAK抑制剂和微管抑制剂联合治疗肿瘤。
本公开另一方面提供了一种治疗肿瘤的方法，该方法包括向有需要的对象施用治疗有效量的FAK抑制剂和微管抑制剂。
本公开又一方面提供了FAK抑制剂和微管抑制剂的药物组合产品，其用于在有需要的对象中治疗肿瘤。
本公开又一方面提供了FAK抑制剂和微管抑制剂在制备用于治疗肿瘤的联用药物中的用途。
本公开又一方面提供了FAK抑制剂在制备用于与微管抑制剂治疗肿瘤 的联用药物中的用途。
本公开又一方面提供了微管抑制剂在制备用于与FAK抑制剂治疗肿瘤的联用药物中的用途。
本公开又一方面提供了FAK抑制剂和微管抑制剂在制备用于联合治疗肿瘤的药物中的用途。
本公开又一方面提供了FAK抑制剂在制备用于与微管抑制剂联合治疗肿瘤的药物中的用途。
本公开又一方面提供了微管抑制剂在制备用于与FAK抑制剂联合治疗肿瘤的药物中的用途。
本公开又一方面提供了一种试剂盒，其包括：FAK抑制剂；和说明书，该说明书指出该FAK抑制剂可用于与微管抑制剂联合治疗肿瘤。
本公开又一方面提供了一种试剂盒，其包括：微管抑制剂；和说明书，该说明书指出该微管抑制剂可用于与FAK抑制剂联合治疗肿瘤。
可选的，所述FAK抑制剂为IN10018、Defactinib、GSK2256098、PF-00562271、VS-4718、APG-2449、AMP945、AMP886或其药学上可接受的盐，优选为IN10018、Defactinib、AMP945、或其药学上可接受的盐，进一步优选为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐，所述IN10018结构如下：
所述Defactinib也称为地法替尼，CAS号为1345713-71-4；所述GSK2256098的CAS号为1224887-10-8。所述PF-00562271的CAS号为717907-75-0；所述VS-4718的CAS号为1061353-68-1；所述APG-2449为亚盛医药研发；所述AMP945的CAS号为1393653-34-3。
可选的，所述微管抑制剂为紫杉类药物、艾瑞布林(Eribulin)、伊沙匹隆(Ixempra)或长春花生物碱。
可选的，所述微管抑制剂为紫杉类药物。
可选的，所述紫杉类药物为多西他赛(Docetaxel)、紫衫醇(Paclitaxel)、 卡巴他赛(Cabazitaxel)或三尖杉宁碱(Cephalomannine)，优选为多西他赛(Docetaxel)或紫衫醇(Paclitaxel)。
可选的，所述微管抑制剂为多西他赛(Docetaxel)。
可选的，所述微管抑制剂为紫衫醇(Paclitaxel)。
所述紫杉醇或者多西他赛均包括其制剂，如紫杉醇脂质体、白蛋白紫杉醇等。
可选的，所述微管抑制剂为艾瑞布林(Eribulin)。所述艾瑞布林也称艾日布林/Eribulin，CAS号为253128-41-5。
可选的，所述免疫检查点抑制剂为抗PD-1/PD-L1抗体、PD-1/PD-L1小分子抑制剂或者TIGIT抑制剂。
可选的，所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，进一步的，所述抗PD-1/PD-L1抗体为帕博利珠单抗(pembrolizumab)、替雷利珠单抗(Tislelizumab)、尼伏单抗(Nivolumab)、特瑞普利单抗(Toripalimab)、阿替利珠单抗(Atezolizumab)、度伐单抗(durvalumab)、阿维单抗(Avelumab)、卡瑞利珠单抗(Camrelizumab)、信迪利单抗(Sintilimab)、西米普利单抗(Cemiplimab)、恩沃利单抗(envafolimab)、BMS-936559、JS003、SHR-1316、GS-4224、AN-4005或者MX-10181。
可选的，所述免疫检查点抑制剂为PD-1/PD-L1小分子抑制剂，进一步的，所述PD-1/PD-L1小分子抑制剂为INCB-086550、拉泽替尼(Lazertinib)、IMMH-010、CA-170、ABSK043或者RRx-001。
可选的，所述免疫检查点抑制剂为TIGIT抑制剂，进一步的，所述TIGIT抑制剂为欧司珀利单抗(Ociperlimab/BGB-A1217)、维博利单抗(Vibostolimab)、domvanalimab(AB154)、替瑞利尤单抗(Tiragolumab)、Belrestotug、艾替利单抗(Etigilimab)、ONO-4686、JS-006、AZD-2936、HLX-301、SEA-TGT、M-6223、IBI-939、COM-902、AB-308、AGEN-1777、AK-127、BAT-6021、BAT-6005、ASP-8374、PM-1022、BMS-986207、HB0036或IBI-321。
可选的，所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂。
可选的，所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微 管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
可选的，所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂。
可选的，所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
可选的，所述FAK抑制剂、所述微管抑制剂和所述免疫检查点抑制剂被同时或依次施用于所述对象。
可选的，所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)。
可选的，所述肿瘤优选为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌。
可选的，其中所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
附图说明
为了更清楚地说明本公开实施例的技术方案，下面将对实施例的附图作简单地介绍，显而易见地，下面描述中的附图仅仅涉及本公开的一些实施例，而非对本发明的限制。
图1显示了FAK沉默后联合0.3μM或1μM Docetaxel 48小时，采用Annexin V试剂盒染色。
图2显示了FAK沉默后联合1μM Docetaxel 48小时后，增强了Calreticulin释放及暴露。
图3显示了FAK沉默后联合0.15μM Eribulin 48小时，采用Annexin V试剂盒染色。
图4显示了FAK沉默后联合0.15μM Eribulin 48小时后，增强了Calreticulin释放及暴露。
图5显示了Docetaxel联合IN10018在结肠癌细胞CT26的IC50值。
图6显示了结肠癌CT26细胞与药物孵育48小时后拍摄细胞的白光显微镜照片。
图7a显示了结肠癌CT26细胞与药物孵育48小时后CRT阳性细胞的百分比；图7b显示了结肠癌CT26细胞与药物孵育48小时后Annexin V阳性细胞的百分比。
图8a显示了小鼠乳腺癌4T1细胞与药物孵育48小时后Calreticulin(CRT)阳性细胞百分比；图8b显示了小鼠乳腺癌4T1细胞与药物孵48小时后Annexin-V阳性细胞百分比；图8c显示了小鼠乳腺癌4T1细胞与药物孵育48小时后GRP94阳性细胞百分比。
图9a显示了小鼠卵巢上皮癌ID8细胞与药物孵育48小时后Calreticulin(CRT)阳性细胞百分比；图9b显示了小鼠卵巢上皮癌ID8细胞与药物孵48小时后Annexin-V阳性细胞百分比。
图10a显示了人卵巢上皮癌TOV-21G细胞与药物孵育48小时后Calreticulin(CRT)阳性细胞百分比；图10b显示了人卵巢上皮癌TOV-21G细胞与药物孵48小时后Annexin-V阳性细胞百分比。
图11a显示了小鼠结肠癌CT26细胞与Docetaxel等药物孵育48小时后Calreticulin(CRT)阳性细胞百分比；图11b显示了小鼠结肠癌CT26细胞与Docetaxel等药物孵48小时后Annexin-V阳性细胞百分比。
图12a显示了小鼠结肠癌CT26细胞与Eribulin等药物孵育48小时后Calreticulin(CRT)阳性细胞百分比；图12b显示了小鼠结肠癌CT26细胞与Eribulin等药物孵48小时后Annexin-V阳性细胞百分比。
图13a显示了小鼠结肠癌CT26细胞与Paclitaxel等药物孵育48小时后Calreticulin(CRT)阳性细胞百分比；图13b显示了小鼠结肠癌CT26细胞与Paclitaxel等药物孵48小时后Annexin-V阳性细胞百分比。
图14a显示了小鼠乳腺癌4T1细胞与Docetaxel等药物孵育48小时后Calreticulin(CRT)阳性细胞百分比；图14b显示了小鼠乳腺癌4T1细胞与Docetaxel等药物孵48小时后Annexin-V阳性细胞百分比。
图15a显示了小鼠乳腺癌4T1细胞与Eribulin等药物孵育48小时后Calreticulin(CRT)阳性细胞百分比；图15b显示了小鼠乳腺癌4T1细胞与Eribulin等药物孵48小时后Annexin-V阳性细胞百分比。
图16显示了在乳腺癌4T1细胞BALB/c小鼠皮下同种移植瘤模型中给予不同受试物后的肿瘤体积的变化。
图17显示了在乳腺癌4T1细胞BALB/c小鼠皮下同种移植瘤模型中给予不同受试物后小鼠体重的变化。
图18a显示了小鼠乳腺癌4T1细胞与Docetaxel等药物孵育48小时后Calreticulin(CRT)阳性细胞百分比；图18b显示了小鼠乳腺癌4T1细胞与Docetaxel等药物孵48小时后Annexin-V阳性细胞百分比。
图19a显示了小鼠乳腺癌4T1细胞与Eribulin等药物孵育48小时后Calreticulin(CRT)阳性细胞百分比；图19b显示了小鼠乳腺癌4T1细胞与Eribulin等药物孵48小时后Annexin-V阳性细胞百分比。
具体实施方式
为使本公开实施例的目的、技术方案和优点更加清楚，下面将结合本公开实施例的附图，对本公开实施例的技术方案进行清楚、完整地描述。显然，所描述的实施例是本公开的一部分实施例，而不是全部的实施例。基于所描述的本公开的实施例，本领域普通技术人员在无需创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明可在不偏离本发明基本属性的情况下以其它具体形式来实施。应该理解的是，在不冲突的前提下，本发明的任一和所有实施方案都可与任一其它实施方案或多个其它实施方案中的技术特征进行组合以得到另外的实施方案。本发明包括这样的组合得到的另外的实施方案。
本公开中提及的所有出版物和专利在此通过引用以它们的全部内容纳入本公开。如果通过引用纳入的任何出版物和专利中使用的用途或术语与本公开中使用的用途或术语冲突，那么以本公开的用途和术语为准。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主 题的限制。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的通常含义。倘若对于某术语存在多个定义，则以本文定义为准。
除了在工作实施例中或另外指出之外，在说明书和权利要求中陈述的定量性质例如剂量的所有数字应理解为在所有情况中被术语“约”修饰。还应理解的是，本申请列举的任何数字范围意在包括该范围内的所有的子范围和该范围或子范围的各个端点的任何组合。
本公开中使用的“包括”、“含有”或者“包含”等类似的词语意指出现该词前面的要素涵盖出现在该词后面列举的要素及其等同，而不排除未记载的要素。本文所用的术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…组成”、或“由…组成”。
定义
本申请中所用的下列术语和符号具有如下所述的含义，其所处的上下文中另有说明的除外。本文所用的术语“FAK抑制剂”是指FAK的有效抑制剂，可适于哺乳动物，特别是人。在一些实施方案中，所述FAK抑制剂为IN10018、Defactinib、GSK2256098、PF-00562271、VS-4718、APG-2449、AMP945、AMP886或其药学上可接受的盐，所述IN10018结构如下：
所述Defactinib也称为地法替尼，CAS号为1345713-71-4；所述GSK2256098的CAS号为1224887-10-8。所述PF-00562271的CAS号为717907-75-0；所述VS-4718的CAS号为1061353-68-1；所述APG-2449为亚盛医药研发；所述AMP945的CAS号为1393653-34-3。在一些实施方案中，所述FAK抑制剂优选为IN10018、Defactinib或其药学上可接受的盐，在一些优选实施方案中，所述FAK抑制剂为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐。
本文所用术语“微管抑制剂”是指微管/微管蛋白的有效抑制剂，可适于哺乳动物，特别是人。微管是细胞骨架的组成部分，遍布细胞质。微管蛋白 是球蛋白小家族中的几个成员之一。微管蛋白超家族包括5个不同的家族，α、β、γ、δ和ε微管蛋白，第六个家族只存在于动植物胚胎原生动物中。微管蛋白家族最常见的成员是α-微管蛋白和β-微管蛋白，它们是构成微管的蛋白质。微管抑制剂与微管蛋白结合促进或抑制微管的装配、干扰微管组成纺锤体的正常结构与功能，具有干扰细胞有丝分裂、抑制细胞增殖的作用，发挥明确的抗肿瘤效应。微管抑制剂是一大类化疗药物，包括紫杉类药物、艾瑞布林、伊沙匹隆和长春花生物碱等。
本文所用术语“紫杉类药物”是指一大类化疗药物，包括从天然树皮提取的药物紫杉醇，也有合成的多西他赛。为了避免歧义，本发明权利要求中所述紫杉醇或者多西他赛均包括其制剂，如紫杉醇脂质体、白蛋白紫杉醇等。
所述艾瑞布林也称艾日布林/Eribulin，CAS号为253128-41-5。
所述伊沙匹隆也称为Ixabepilone、azaepothilone B或者BMS-247550，CAS号为219989-84-1。
本文所用的术语“免疫检查点抑制剂”是指能够通过调控免疫检查点通路(例如PD-1、TIGIT、CTLA-4、LAG-3、TIM-3等)来提高免疫系统活性的药物。在一些实施方案中，免疫检查点抑制剂为PD-1/PD-L1(程序性细胞死亡蛋白1)通路的拮抗剂(也称为“PD-1抑制剂”)或TIGIT抑制剂。PD-1抑制剂在本公开中也称为PD-1/PD-L1抑制剂。例如，在本公开的治疗方法、药物和用途中，所述PD-1/PD-L1抑制剂为PD-1/PD-L1抗体，所述PD-1/PD-L1抗体包括但不限于帕博利珠单抗(可瑞达/Keytruda/K药)、替雷利珠单抗(Tislelizumab/百泽安)、尼伏单抗(Nivolumab)、特瑞普利单抗(Toripalimab/拓益)、度伐单抗(英飞凡/度伐鲁单抗/durvalumab)、阿维单抗(Avelumab/Bavencio)、阿替利珠单抗(MPDL3280A/Atezolizumab/Tecentriq/T药)、BMS-936559(全人源抗PD-L1的IgG4单克隆抗体)、GS-4224、AN-4005或者MX-10181。在一些优选的实施方案中，PD-1抑制剂为特瑞普利单抗。在一些实施方案中，PD-1抑制剂用于治疗人对象。在一些实施方案中，PD-1为人PD-1。
PD-1/PD-L1抑制剂也包括PD-1/PD-L1小分子抑制剂，在一些实施方案中，所述PD-1/PD-L1小分子抑制剂为INCB-086550、拉泽替尼(Lazertinib)、IMMH-010、CA-170、ABSK043或者RRx-001。
TIGIT(也称为WUCAM、Vstm3、VSIG9)是Ig超家族的一种受体，是继 PD-1/PD-L1之后的新型免疫检查点。例如，在本公开的治疗方法、药物和用途中，所述PD-1/PD-L1抑制剂为TIGIT抑制剂，所述TIGIT抑制剂包括但不限于欧司珀利单抗(Ociperlimab/BGB-A1217)、维博利单抗(Vibostolimab)、domvanalimab(AB154)、替瑞利尤单抗(Tiragolumab)、Belrestotug、艾替利单抗(Etigilimab)、ONO-4686、JS-006、AZD-2936、HLX-301、SEA-TGT、M-6223、IBI-939、COM-902、AB-308、AGEN-1777、AK-127、BAT-6021、BAT-6005、ASP-8374、PM-1022、BMS-986207、HB0036或IBI-321。在一些实施方案中，TIGIT抑制剂用于治疗人对象。为了避免歧义，本文中抗体均包括双抗。
本文所用的“药物组合”或者“药物组合产品”既可以指采用一个剂量单位形式的固定组合(例如所有药物活性成分以一种剂型存在)或者成套药盒以组合施用的产品的情形，也可以指一种药物与指示该药物可与另外的一种或多种药物联合使用的说明书的组合情形。
本文所用的“联合治疗”或者“联用药物”是指一种药物与另外的一种或多种药物联合使用来治疗疾病，既包括一种药物与另外的一种或多种药物的组合的情形，也包括一种药物与指示该药物可与另外的一种或多种药物联合使用的说明书的组合情形。
“同时或依次施用”在本申请中是指一个给药周期内(例如4周内、3周内、2周内、1周内或24小时以内)两种以上的药物同时或以一定时间间隔先后施用，药物施用的方式(例如口服、静脉、肌肉或皮下施用等)可以相同或不同，两种以上的药物的给药频率/周期可以相同或不同。当本公开的治疗方法、产品或用途涉及两种药物时，两种药物可同时或以一定时间间隔分别单独施用。当本公开的治疗方法、产品或用途涉及三种药物时，三种药物可以在同一时间点施用，或者两种药物在一个时间点施用而剩下一种药物在另一个时间点施用，或者所有三种药物各自在不同时间点施用。
在一些实施方案中，PD-1/PD-L1抑制剂被静脉(例如，作为静脉输注)或皮下施用或口服。优选地，PD-1/PD-L1抑制剂以静脉输注施用。
在一些实施方案中，TIGIT抑制剂被静脉(例如，作为静脉输注)或皮下施用或口服。优选地，TIGIT抑制剂以静脉输注施用。
免疫检查点抑制剂治疗癌症的能力取决于肿瘤组织内肿瘤抗原特异性T细胞的存在。这要求肿瘤组织表达将自身与其非转化的对应物区分开来的抗 原，例如，通过被称为新抗原(neoantigen)的新型蛋白产物。肿瘤新抗原负荷与免疫原性和敏感性(例如，对检查点抑制剂疗法的敏感性)密切相关，这意味着免疫原性较差的肿瘤应该在很大程度上对这些药物耐药。用于释放可被APC摄取的肿瘤抗原的疗法，如诱导免疫原性细胞死亡(ICD)的那些，可能会促进有效的抗肿瘤免疫，特别是当进一步与检查点抑制剂联合时。
本文所用的术语“治疗”是指给患有疾病或者具有所述疾病的症状的对象施用一种或多种药物物质，用以治愈、缓解、减轻、改变、医治、改善、改进或影响所述疾病或者所述疾病的症状。在一些实施方案中，所述疾病是肿瘤或者癌症。
本文所用的术语“肿瘤”是指机体在各种致瘤因素的作用下，局部组织的细胞在基因水平上失去对其生长的正常调控，从而导致其克隆型异常增生而形成的异常病变。所述肿瘤包括，但不限于：膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)。在一些实施方案中，所述肿瘤优选为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌；在一些实施方案中，所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
本文所用的术语“对象”或“受试者”是指哺乳动物和非哺乳动物。哺乳动物是指哺乳类的任何成员，其包括但不限于：人；非人灵长类动物，如黑猩猩及其它猿类和猴类物种；农场动物，如牛、马、绵羊、山羊和猪；家畜，如兔、狗和猫；实验室动物，包括啮齿类动物，如大鼠、小鼠和豚鼠；等等。非哺乳动物的例子包括但不限于鸟等。术语“对象”并不限定特定的年龄或性别。在一些实施方案中，对象是人。
本文所用的术语“药学上可接受的”指的是无毒的、生物学上可耐受的，适合给对象施用的。
本文所用的术语“药学上可接受的盐”指的是无毒的、生物学上可耐受的适合给对象施用的酸加成盐，包括但不限于：与无机酸形成的酸加成盐，例如盐酸盐、氢溴酸盐、碳酸盐、碳酸氢盐、磷酸盐、硫酸盐、亚硫酸盐、硝酸盐等；以及与有机酸形成的酸加成盐，例如甲酸盐、乙酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和与式HOOC-(CH2)n-COOH(其中n是0-4)的链烷二羧酸形成的盐等。
此外，药学上可接受的酸加成盐可以按照由碱性化合物制备酸加成盐的常规操作通过将游离碱溶于合适的溶剂并且用酸处理该溶液来得到。本领域技术人员无需过多实验即可确定各种可用来制备无毒的药学上可接受的酸加成盐的合成方法。
本文所用的术语“药学上可接受的组合物”是指必须在化学和/或毒理学上与包括制剂的其他成分相容，和/或与接受其治疗的对象相容。本文所用的术语“治疗有效量”是指通常足以对对象产生有益治疗效果的量。可以通过常规方法(例如建模、剂量递增研究或临床试验)结合常规影响因素(例如给药方式、化合物的药代动力学、疾病的严重程度和病程、对象的病史、对象的健康状况、对象对药物的响应程度等)来确定本发明的治疗有效量。
本文所用的术语“抑制”是指生物活动或过程的基线活性的降低。
本文所用的术语“试剂盒”是指用于盛放检测化学成分、药物残留、病毒种类等化学试剂的盒子。本发明所述试剂盒可以是包括(i)FAK抑制剂、微管抑制剂和免疫检查点抑制剂中的一种、二种或三种；以及(ii)说明书，所述说明书指出可使用FAK抑制剂、微管抑制剂和免疫检查点抑制剂来在对象中治疗肿瘤。在一种实施方案中，试剂盒包括(i)FAK抑制剂；以及(ii)说明书，所述说明书指出可使用FAK抑制剂、微管抑制剂和免疫检查点抑制剂来在对象中治疗肿瘤。在一种实施方案中，试剂盒包括(i)微管抑制剂；以及(ii)说明书，所述说明书指出可使用FAK抑制剂、微管抑制剂和免疫检查点抑制剂来在对象中治疗肿瘤。在一种实施方案中，试剂盒包括(i)免疫检查点抑制剂；以及(ii)说明书，所述说明书指出可使用FAK抑制剂、微管抑制剂和免疫检查点抑制剂来在对象中治疗肿瘤。在一种实施方案中，试剂盒包括 (i)FAK抑制剂、微管抑制剂和免疫检查点抑制剂；以及(ii)说明书，所述说明书指出可使用FAK抑制剂、微管抑制剂和免疫检查点抑制剂来在对象中治疗肿瘤。在一种实施方案中，试剂盒包括(i)FAK抑制剂；以及(ii)说明书，所述说明书指出可使用FAK抑制剂和微管抑制剂来在对象中治疗肿瘤。在一种实施方案中，试剂盒包括(i)微管抑制剂；以及(ii)说明书，所述说明书指出可使用微管抑制剂和FAK抑制剂在对象中治疗肿瘤。
试剂盒的化合物可以包含在分开的容器中。可选地，两种或更多种化合物包含在同一容器中。例如，试剂盒可以包括第一容器、第二容器、第三容器和包装插页，其中第一容器包括至少一个剂量的包括FAK抑制剂的药物，第二容器包括至少一个剂量的微管抑制剂，第三容器包括至少一个剂量的免疫检查点抑制剂的药物，且所述包装插页包括使用药物治疗对象的肿瘤的说明。第一容器、第二容器和第三容器可以包含相同或不同形状(例如，小瓶、注射器和瓶)和/或材料(例如，塑料或玻璃)。试剂盒还可以包括可以有助于施用药物的其他材料，如稀释剂、过滤器、IV袋和管线、针和注射器。
给予受试者的FAK抑制剂、微管抑制剂、或免疫检查点抑制剂的精确量将取决于各种因素，例如给定的药物或化合物，药物制剂，给药途径，疾病类型，病症，所治疗的受试者或宿主的身份等，但是仍然可以由本领域技术人员常规确定。例如，确定有效量还取决于细胞增殖的程度，严重性和类型。技术人员将能够根据这些和其他因素确定合适的剂量。
FAK抑制剂、微管抑制剂、或免疫检查点抑制剂可选择合适的方式例如口服、静脉、肌肉或皮下施用给药。
例如，口服给药时，可以将药物与药学上可接受的载体例如惰性稀释剂或可吸收的食用载体一起口服给药。它们可以封装在硬壳或软壳明胶胶囊中，可以压制成片剂，或者可以直接与患者的食物混合。例如，药物可以与一种或多种赋形剂组合，并以可摄取的片剂，口腔片剂，锭剂，胶囊，酏剂，悬浮液，糖浆或糯米纸囊剂等形式使用。片剂，锭剂，丸剂，胶囊剂等可进一步包括：粘合剂，例如黄芪胶，阿拉伯胶，玉米淀粉或明胶；赋形剂，如磷酸二钙；崩解剂，例如玉米淀粉，马铃薯淀粉，海藻酸等；润滑剂，例如硬脂酸镁；或甜味剂，例如蔗糖，果糖，乳糖或阿斯巴甜；或调味剂。
例如，输注或注射静脉内或腹膜内给药时，药物的溶液可以在水中制备，任选地与无毒的表面活性剂混合。
用于注射或输注的示例性药物剂型包括：无菌水溶液，分散液，或包含活性成分的无菌粉末，该无菌粉末适合于临时制备无菌注射或输注溶液或分散液。无论如何，最终剂型在生产和储存条件下均应无菌，流动且稳定。
无菌注射溶液可以通过将所需量的药物与所需的上述各种其他成分掺入适当的溶剂中，然后过滤灭菌来制备。对于用于制备无菌注射溶液的无菌粉末，优选的制备方法可以是真空干燥和冷冻干燥技术，其可以产生活性成分加上先前无菌过滤后存在的任何其他所需成分的粉末。
用于治疗所需的FAK抑制剂、微管抑制剂、或免疫检查点抑制剂的量不仅可以随所选择的特定试剂而变化，还可以随给药途径，所治疗疾病的性质以及患者的年龄和状况而变化，并且最终可以由主治医师或临床医生自行决定。然而，一般而言，剂量可以在每天约0.1至约50mg/kg体重的范围内。
所述FAK抑制剂以成年人中5mg/天-300mg/天的剂量范围施用。在一种具体的实施方案中，IN10018或其药学上可接受盐以成年人中5mg/天-100mg/天的剂量施用，在一种具体的实施方案中，IN10018或其药学上可接受盐以成年人中25mg/天-100mg/天的剂量施用，所述剂量以游离碱计。
所述微管抑制剂以成年人中每周20-60mg/m2的剂量范围施用。在一种具体的实施方式中，多西他赛以成年人中每周20-25mg/m2的剂量施用；紫衫醇或其制剂以成年人中每周45-60mg/m2的剂量施用，用量以紫衫醇计；艾瑞布林(Eribulin)以1.4mg/m2静脉历时2至5分钟在21天疗程的第1天和第8天施用。
所述免疫检查点抑制剂每次给药以成年人中2-10mg/kg或者50-1200mg的剂量施用，每2周到3周给药一次。在一种具体的实施方式中，所述免疫检查点抑制剂每次给药以成年人中3-10mg/kg或者100-1200mg的剂量施用，每2周到3周给药一次。
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
在一些实施方案中，本公开还公开了以下：
1.FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其用于在对象中治疗肿瘤的方法。
2.如实施方案1所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述FAK抑制剂为IN10018、Defactinib、GSK2256098、PF-00562271、 VS-4718、APG-2449、AMP945、AMP886或其药学上可接受的盐，优选为IN10018、Defactinib、AMP945、或其药学上可接受的盐，进一步优选为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐，所述IN10018结构如下：
3.如实施方案1-2所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述微管抑制剂为紫杉类药物、艾瑞布林(Eribulin)、伊沙匹隆(Ixempra)或长春花生物碱。
4.如实施方案1-3任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述微管抑制剂为紫杉类药物。
5.如实施方案3-4任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述紫杉类药物为多西他赛(Docetaxel)、紫衫醇(Paclitaxel)、卡巴他赛(Cabazitaxel)或三尖杉宁碱(Cephalomannine)，优选为多西他赛(Docetaxel)或紫衫醇(Paclitaxel)。
6.如实施方案1-5任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述微管抑制剂为多西他赛(Docetaxel)。
7.如实施方案1-5任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述微管抑制剂为紫衫醇(Paclitaxel)。
8.如实施方案1-4任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述微管抑制剂为艾瑞布林(Eribulin)。
9.如实施方案1-8任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体、PD-1/PD-L1小分子抑制剂或者TIGIT抑制剂。
10.如实施方案1-9任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，进一步的，所述抗PD-1/PD-L1抗体为帕博利珠单抗(pembrolizumab)、替雷利珠单抗(Tislelizumab)、尼伏单抗(Nivolumab)、特瑞普利单抗(Toripalimab)、阿替利 珠单抗(Atezolizumab)、度伐单抗(durvalumab)、阿维单抗(Avelumab)、卡瑞利珠单抗(Camrelizumab)、信迪利单抗(Sintilimab)、西米普利单抗(Cemiplimab)、恩沃利单抗(envafolimab)、BMS-936559、JS003、SHR-1316、GS-4224、AN-4005或者MX-10181。
11.如实施方案1-9任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，所述免疫检查点抑制剂为PD-1/PD-L1小分子抑制剂，进一步的，所述PD-1/PD-L1小分子抑制剂为INCB-086550、拉泽替尼(Lazertinib)、IMMH-010、CA-170、ABSK043或者RRx-001。
12.如实施方案1-9任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述免疫检查点抑制剂为TIGIT抑制剂，进一步的，所述TIGIT抑制剂为欧司珀利单抗(Ociperlimab/BGB-A1217)、维博利单抗(Vibostolimab)、domvanalimab(AB154)、替瑞利尤单抗(Tiragolumab)、Belrestotug、艾替利单抗(Etigilimab)、ONO-4686、JS-006、AZD-2936、HLX-301、SEA-TGT、M-6223、IBI-939、COM-902、AB-308、AGEN-1777、AK-127、BAT-6021、BAT-6005、ASP-8374、PM-1022、BMS-986207、HB0036或IBI-321。
13.如实施方案1所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
14.如实施方案1所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
15.如实施方案1-14任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，所述FAK抑制剂、所述微管抑制剂和所述免疫检查点抑制剂被同时或依次施用于所述对象。
16.如实施方案1-15任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选地，所述肿瘤为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌。
17.如实施方案1-16任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
18.一种试剂盒或药学上可接受的组合物，其包括：
(a)FAK抑制剂；
(b)微管抑制剂；和
(c)免疫检查点抑制剂。
19.如实施方案18所述的试剂盒或组合物，其中所述FAK抑制剂为IN10018、Defactinib、GSK2256098、PF-00562271、VS-4718、APG-2449、AMP945、AMP886或其药学上可接受的盐，优选为IN10018、Defactinib、AMP945、或其药学上可接受的盐，进一步优选为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐，所述IN10018结构如下：
20.如实施方案18-19所述的试剂盒或组合物，其中所述微管抑制剂为紫杉类药物、艾瑞布林(Eribulin)、伊沙匹隆(Ixempra)或长春花生物碱。
21.如实施方案18-20任一项所述的试剂盒或组合物，其中所述微管抑制剂为紫杉类药物。
22.如实施方案20-21任一项所述的试剂盒或组合物，其中所述紫杉类药物为多西他赛(Docetaxel)、紫衫醇(Paclitaxel)、卡巴他赛(Cabazitaxel)或三尖杉宁碱(Cephalomannine)，优选为多西他赛(Docetaxel)或紫衫醇(Paclitaxel)。
23.如实施方案18-22任一项所述的试剂盒或组合物，其中所述微管抑制剂为多西他赛(Docetaxel)。
24.如实施方案18-22任一项所述的试剂盒或组合物，其中所述微管抑制剂为紫衫醇(Paclitaxel)。
25.如实施方案18-22任一项所述的试剂盒或组合物，其中所述微管抑制剂为艾瑞布林(Eribulin)。
26.如实施方案18-25任一项所述的试剂盒或组合物，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体、PD-1/PD-L1小分子抑制剂或者TIGIT抑制剂。
27.如实施方案18-26任一项所述的试剂盒或组合物，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，进一步的，所述抗PD-1/PD-L1抗体为帕博利珠单抗(pembrolizumab)、替雷利珠单抗(Tislelizumab)、尼伏单抗(Nivolumab)、特瑞普利单抗(Toripalimab)、阿替利珠单抗(Atezolizumab)、度伐单抗(durvalumab)、阿维单抗(Avelumab)、卡瑞利珠单抗(Camrelizumab)、信迪利单抗(Sintilimab)、西米普利单抗(Cemiplimab)、恩沃利单抗(envafolimab)、BMS-936559、JS003、SHR-1316、GS-4224、AN-4005或者MX-10181。
28.如实施方案18-26任一项所述的试剂盒或组合物，所述免疫检查点抑制剂为PD-1/PD-L1小分子抑制剂，进一步的，所述PD-1/PD-L1小分子抑制剂为INCB-086550、拉泽替尼(Lazertinib)、IMMH-010、CA-170、ABSK043或者RRx-001。
29.如实施方案18-26任一项所述的试剂盒或组合物，其中所述免疫检查点抑制剂为TIGIT抑制剂，进一步的，所述TIGIT抑制剂为欧司珀利单抗(Ociperlimab/BGB-A1217)、维博利单抗(Vibostolimab)、domvanalimab(AB154)、替瑞利尤单抗(Tiragolumab)、Belrestotug、艾替利单抗(Etigilimab)、ONO-4686、JS-006、AZD-2936、HLX-301、SEA-TGT、M-6223、 IBI-939、COM-902、AB-308、AGEN-1777、AK-127、BAT-6021、BAT-6005、ASP-8374、PM-1022、BMS-986207、HB0036或IBI-321。
30.如实施方案18所述的试剂盒或组合物，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
31.如实施方案18所述的试剂盒或组合物，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
32.如实施方案18-31任一项所述的试剂盒或组合物，其中所述组合物用于药物。
33.如实施方案32所述的试剂盒或组合物，其中所述药物用于治疗肿瘤，所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选地，所述肿瘤为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌。
34.如实施方案33所述的试剂盒或组合物，其中所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
35.一种在对象中治疗肿瘤的方法，其中所述方法包括向所述对象施用治疗有效量的FAK抑制剂、微管抑制剂和免疫检查点抑制剂。
36.如实施方案35所述的方法，其中所述FAK抑制剂为IN10018、Defactinib、GSK2256098、PF-00562271、VS-4718、APG-2449、AMP945、AMP886或其药学上可接受的盐，优选为IN10018、Defactinib、AMP945、或其药学上可接受的盐，进一步优选为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐，所述IN10018结构如下：
37.如实施方案35-36所述的方法，其中所述微管抑制剂为紫杉类药物、艾瑞布林(Eribulin)、伊沙匹隆(Ixempra)或长春花生物碱。
38.如实施方案35-37任一项所述的方法，其中所述微管抑制剂为紫杉类药物。
39.如实施方案37-38任一项所述的方法，其中所述紫杉类药物为多西他赛(Docetaxel)、紫衫醇(Paclitaxel)、卡巴他赛(Cabazitaxel)或三尖杉宁碱(Cephalomannine)，优选为多西他赛(Docetaxel)或紫衫醇(Paclitaxel)。
40.如实施方案35-39任一项所述的方法，其中所述微管抑制剂为多西他赛(Docetaxel)。
41.如实施方案35-39任一项所述的方法，其中所述微管抑制剂为紫衫醇(Paclitaxel)。
42.如实施方案35-37任一项所述的方法，其中所述微管抑制剂为艾瑞布林(Eribulin)。
43.如实施方案35-42任一项所述的方法，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体、PD-1/PD-L1小分子抑制剂或者TIGIT抑制剂。
44.如实施方案35-43任一项所述的方法，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，进一步的，所述抗PD-1/PD-L1抗体为帕博利珠单抗(pembrolizumab)、替雷利珠单抗(Tislelizumab)、尼伏单抗(Nivolumab)、特瑞普利单抗(Toripalimab)、阿替利珠单抗(Atezolizumab)、度伐单抗(durvalumab)、阿维单抗(Avelumab)、卡瑞利珠单抗(Camrelizumab)、信迪利单抗(Sintilimab)、西米普利单抗(Cemiplimab)、恩沃利单抗(envafolimab)、BMS-936559、JS003、 SHR-1316、GS-4224、AN-4005或者MX-10181。
45.如实施方案35-43任一项所述的方法，所述免疫检查点抑制剂为PD-1/PD-L1小分子抑制剂，进一步的，所述PD-1/PD-L1小分子抑制剂为INCB-086550、拉泽替尼(Lazertinib)、IMMH-010、CA-170、ABSK043或者RRx-001。
46.如实施方案35-43任一项所述的方法，其中所述免疫检查点抑制剂为TIGIT抑制剂，进一步的，所述TIGIT抑制剂为欧司珀利单抗(Ociperlimab/BGB-A1217)、维博利单抗(Vibostolimab)、domvanalimab(AB154)、替瑞利尤单抗(Tiragolumab)、Belrestotug、艾替利单抗(Etigilimab)、ONO-4686、JS-006、AZD-2936、HLX-301、SEA-TGT、M-6223、IBI-939、COM-902、AB-308、AGEN-1777、AK-127、BAT-6021、BAT-6005、ASP-8374、PM-1022、BMS-986207、HB0036或IBI-321。
47.如实施方案35所述的方法，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
48.如实施方案35所述的方法，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
49.如实施方案35-48任一项所述的方法，所述FAK抑制剂、所述微管抑制剂和所述免疫检查点抑制剂被同时或依次施用于所述对象。
50.如实施方案35-49任一项所述的方法，其中所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞 淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选地，所述肿瘤为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌。
51.如实施方案35-50任一项所述的方法，其中所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
52.FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其用于通过在对象中增加免疫原性细胞死亡来治疗肿瘤的方法。
53.如实施方案52所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述FAK抑制剂为IN10018、Defactinib、GSK2256098、PF-00562271、VS-4718、APG-2449、AMP945、AMP886或其药学上可接受的盐，优选为IN10018、Defactinib、AMP945、或其药学上可接受的盐，进一步优选为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐，所述IN10018结构如下：
54.如实施方案52-53所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述微管抑制剂为紫杉类药物、艾瑞布林(Eribulin)、伊沙匹隆(Ixempra)或长春花生物碱。
55.如实施方案52-54任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述微管抑制剂为紫杉类药物。
56.如实施方案54-55任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述紫杉类药物为多西他赛(Docetaxel)、紫衫醇(Paclitaxel)、卡巴他赛(Cabazitaxel)或三尖杉宁碱(Cephalomannine)，优选为多西他赛(Docetaxel)或紫衫醇(Paclitaxel)。
57.如实施方案52-56任一项所述的FAK抑制剂、微管抑制剂和免疫检 查点抑制剂，其中所述微管抑制剂为多西他赛(Docetaxel)。
58.如实施方案52-56任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述微管抑制剂为紫衫醇(Paclitaxel)。
59.如实施方案52-54任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述微管抑制剂为艾瑞布林(Eribulin)。
60.如实施方案52-59任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体、PD-1/PD-L1小分子抑制剂或者TIGIT抑制剂。
61.如实施方案52-60任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，进一步的，所述抗PD-1/PD-L1抗体为帕博利珠单抗(pembrolizumab)、替雷利珠单抗(Tislelizumab)、尼伏单抗(Nivolumab)、特瑞普利单抗(Toripalimab)、阿替利珠单抗(Atezolizumab)、度伐单抗(durvalumab)、阿维单抗(Avelumab)、卡瑞利珠单抗(Camrelizumab)、信迪利单抗(Sintilimab)、西米普利单抗(Cemiplimab)、恩沃利单抗(envafolimab)、BMS-936559、JS003、SHR-1316、GS-4224、AN-4005或者MX-10181。
62.如实施方案52-60任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，所述免疫检查点抑制剂为PD-1/PD-L1小分子抑制剂，进一步的，所述PD-1/PD-L1小分子抑制剂为INCB-086550、拉泽替尼(Lazertinib)、IMMH-010、CA-170、ABSK043或者RRx-001。
63.如实施方案52-60任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述免疫检查点抑制剂为TIGIT抑制剂，进一步的，所述TIGIT抑制剂为欧司珀利单抗(Ociperlimab/BGB-A1217)、维博利单抗(Vibostolimab)、domvanalimab(AB154)、替瑞利尤单抗(Tiragolumab)、Belrestotug、艾替利单抗(Etigilimab)、ONO-4686、JS-006、AZD-2936、HLX-301、SEA-TGT、M-6223、IBI-939、COM-902、AB-308、AGEN-1777、AK-127、BAT-6021、BAT-6005、ASP-8374、PM-1022、BMS-986207、HB0036或IBI-321。
64.如实施方案52所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体 或PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
65.如实施方案52所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
66.如实施方案52-65任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，所述FAK抑制剂、所述微管抑制剂和所述免疫检查点抑制剂被同时或依次施用于所述对象。
67.如实施方案52-66任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选地，所述肿瘤为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌。
68.如实施方案52-67任一项所述的FAK抑制剂、微管抑制剂和免疫检查点抑制剂，其中所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
69.一种通过在对象中增加免疫原性细胞死亡来治疗肿瘤的方法，其中所述方法包括向所述对象施用治疗有效量的FAK抑制剂、微管抑制剂和免疫检查点抑制剂。
70.如实施方案69所述的方法，其中所述FAK抑制剂为IN10018、 Defactinib、GSK2256098、PF-00562271、VS-4718、APG-2449、AMP945、AMP886或其药学上可接受的盐，优选为IN10018、Defactinib、AMP945、或其药学上可接受的盐，进一步优选为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐，所述IN10018结构如下：
71.如实施方案69-70所述的方法，其中所述微管抑制剂为紫杉类药物、艾瑞布林(Eribulin)、伊沙匹隆(Ixempra)或长春花生物碱。
72.如实施方案69-71任一项所述的方法，其中所述微管抑制剂为紫杉类药物。
73如实施方案71-72任一项所述的方法，其中所述紫杉类药物为多西他赛(Docetaxel)、紫衫醇(Paclitaxel)、卡巴他赛(Cabazitaxel)或三尖杉宁碱(Cephalomannine)，优选为多西他赛(Docetaxel)或紫衫醇(Paclitaxel)。
74.如实施方案69-73任一项所述的方法，其中所述微管抑制剂为多西他赛(Docetaxel)。
75.如实施方案69-73任一项所述的方法，其中所述微管抑制剂为紫衫醇(Paclitaxel)。
76.如实施方案69-73任一项所述的方法，其中所述微管抑制剂为艾瑞布林(Eribulin)。
77.如实施方案69-76任一项所述的方法，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体、PD-1/PD-L1小分子抑制剂或者TIGIT抑制剂。
78.如实施方案69-77任一项所述的方法，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，进一步的，所述抗PD-1/PD-L1抗体为帕博利珠单抗(pembrolizumab)、替雷利珠单抗(Tislelizumab)、尼伏单抗(Nivolumab)、特瑞普利单抗(Toripalimab)、阿替利珠单抗(Atezolizumab)、度伐单抗(durvalumab)、阿维单抗(Avelumab)、卡瑞利珠单抗(Camrelizumab)、信迪利单抗(Sintilimab)、西米普利单抗(Cemiplimab)、恩沃利单抗(envafolimab)、BMS-936559、JS003、SHR-1316、GS-4224、AN-4005或者MX-10181。
79.如实施方案69-77任一项所述的方法，所述免疫检查点抑制剂为PD-1/PD-L1小分子抑制剂，进一步的，所述PD-1/PD-L1小分子抑制剂为INCB-086550、拉泽替尼(Lazertinib)、IMMH-010、CA-170、ABSK043或者RRx-001。
80.如实施方案69-77任一项所述的方法，其中所述免疫检查点抑制剂为TIGIT抑制剂，进一步的，所述TIGIT抑制剂为欧司珀利单抗(Ociperlimab/BGB-A1217)、维博利单抗(Vibostolimab)、domvanalimab(AB154)、替瑞利尤单抗(Tiragolumab)、Belrestotug、艾替利单抗(Etigilimab)、ONO-4686、JS-006、AZD-2936、HLX-301、SEA-TGT、M-6223、IBI-939、COM-902、AB-308、AGEN-1777、AK-127、BAT-6021、BAT-6005、ASP-8374、PM-1022、BMS-986207、HB0036或IBI-321。
81.如实施方案69所述的方法，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
82.如实施方案69所述的方法，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是，所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
83.如实施方案69-82任一项所述的方法，所述FAK抑制剂、所述微管抑制剂和所述免疫检查点抑制剂被同时或依次施用于所述对象。
84.如实施方案69-83任一项所述的方法，其中所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或 者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选地，所述肿瘤为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌。
85.如实施方案69-84任一项所述的方法，其中所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
86.FAK抑制剂在制备用于在对象中治疗肿瘤的药物中的用途，其中将所述FAK抑制剂、微管抑制剂和免疫检查点抑制剂施用于所述对象。
87.微管抑制剂在制备用于在对象中治疗肿瘤的药物中的用途，其中将FAK抑制剂，所述微管抑制剂和免疫检查点抑制剂施用于所述对象。
88.免疫检查点抑制剂在制备用于在对象中治疗肿瘤的药物中的用途，其中将FAK抑制剂、微管抑制剂和所述免疫检查点抑制剂施用于所述对象。
89.FAK抑制剂、微管抑制剂和免疫检查点抑制剂在制备用于治疗肿瘤的联用药物中的用途。
90.FAK抑制剂在制备用于与微管抑制剂和免疫检查点抑制剂治疗肿瘤的联用药物中的用途。
91.微管抑制剂在制备用于与FAK抑制剂和免疫检查点抑制剂治疗肿瘤的联用药物中的用途。
92.免疫检查点抑制剂在制备用于与FAK抑制剂和微管抑制剂治疗肿瘤的联用药物中的用途。
93.FAK抑制剂、微管抑制剂和免疫检查点抑制剂在制备用于联合治疗肿瘤的药物中的用途。
94.FAK抑制剂在制备用于与微管抑制剂和免疫检查点抑制剂联合治疗肿瘤的药物中的用途。
95.微管抑制剂在制备用于与FAK抑制剂和免疫检查点抑制剂联合治疗肿瘤的药物中的用途。
96.免疫检查点抑制剂在制备用于与FAK抑制剂和微管抑制剂联合治疗肿瘤的药物中的用途。
97.如实施方案86-96任一项所述的用途，其中所述FAK抑制剂为IN10018、Defactinib、GSK2256098、PF-00562271、VS-4718、APG-2449、 AMP945、AMP886或其药学上可接受的盐，优选为IN10018、Defactinib、AMP945、或其药学上可接受的盐，进一步优选为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐，所述IN10018结构如下：
98.如实施方案86-97任一项所述的用途，其中所述微管抑制剂为紫杉类药物、艾瑞布林(Eribulin)、伊沙匹隆(Ixempra)或长春花生物碱。
99.如实施方案86-98任一项所述的用途，其中所述微管抑制剂为紫杉类药物。
100.如实施方案98-99任一项所述的用途，其中所述紫杉类药物为多西他赛(Docetaxel)、紫衫醇(Paclitaxel)、卡巴他赛(Cabazitaxel)或三尖杉宁碱(Cephalomannine)，优选为多西他赛(Docetaxel)或紫衫醇(Paclitaxel)。
101.如实施方案98-100任一项所述的用途，其中所述微管抑制剂为多西他赛(Docetaxel)。
102.如实施方案98-100任一项所述的用途，其中所述微管抑制剂为紫衫醇(Paclitaxel)。
103.如实施方案98-100任一项所述的用途，其中所述微管抑制剂为艾瑞布林(Eribulin)。
104.如实施方案98-103任一项所述的用途，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体、PD-1/PD-L1小分子抑制剂或者TIGIT抑制剂。
105.如实施方案98-104任一项所述的用途，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，进一步的，所述抗PD-1/PD-L1抗体为帕博利珠单抗(pembrolizumab)、替雷利珠单抗(Tislelizumab)、尼伏单抗(Nivolumab)、特瑞普利单抗(Toripalimab)、阿替利珠单抗(Atezolizumab)、度伐单抗(durvalumab)、阿维单抗(Avelumab)、卡瑞利珠单抗(Camrelizumab)、信迪利单抗(Sintilimab)、西米普利单抗(Cemiplimab)、恩沃利单抗(envafolimab)、BMS-936559、JS003、SHR-1316、GS-4224、AN-4005或者MX-10181。
106.如实施方案98-104任一项所述的用途，所述免疫检查点抑制剂为 PD-1/PD-L1小分子抑制剂，进一步的，所述PD-1/PD-L1小分子抑制剂为INCB-086550、拉泽替尼(Lazertinib)、IMMH-010、CA-170、ABSK043或者RRx-001。
107.如实施方案98-104任一项所述的用途，其中所述免疫检查点抑制剂为TIGIT抑制剂，进一步的，所述TIGIT抑制剂为欧司珀利单抗(Ociperlimab/BGB-A1217)、维博利单抗(Vibostolimab)、domvanalimab(AB154)、替瑞利尤单抗(Tiragolumab)、Belrestotug、艾替利单抗(Etigilimab)、ONO-4686、JS-006、AZD-2936、HLX-301、SEA-TGT、M-6223、IBI-939、COM-902、AB-308、AGEN-1777、AK-127、BAT-6021、BAT-6005、ASP-8374、PM-1022、BMS-986207、HB0036或IBI-321。
108.如实施方案98-107任一项所述的用途，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
109.如实施方案98-107任一项所述的用途，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
110.如实施方案98-109任一项所述的用途，所述FAK抑制剂、所述微管抑制剂和所述免疫检查点抑制剂被同时或依次施用于所述对象。
111.如实施方案86-110任一项所述的用途，其中所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病 (ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选地，所述肿瘤为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌。
112.如实施方案98-111任一项所述的用途，其中所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
实施例
提供下面的实施例以进一步阐述本发明。应理解，这些实施例仅用于举例说明本发明，而不用于限制本发明的范围。
下列实施例中未注明具体条件的实验方法均可以按照这类反应的常规条件进行或者按照制造厂商所建议的条件进行。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例中所用的缩写含义如下：

实施例1：FAK靶点抑制增强卵巢癌细胞针对Docetaxel免疫原性细胞死亡的研究
实验方案：
1.FAK沉默，联合Docetaxel促进卵巢癌细胞HCC827凋亡
体外实验利用siRNA技术降低FAK的表达水平，与Docetaxel联合使用48小时；利用流式细胞仪，检测对照(DMSO)和FAK沉默的细胞凋亡
2.FAK沉默，联合Docetaxel能够有效促进卵巢癌细胞SK-OV-3产生ICD作用
体外实验利用siRNA技术降低FAK的表达水平，与Docetaxel联合使用48小时，利用流式细胞仪，检测ICD的主要靶标Calreticulin的表达情况。
实验抗体：重组Alexa647荧光Anti-Calreticulin(抗-钙网蛋白)抗体(Abcam，ab196159)，Annexin V细胞凋亡检测试剂盒(Invitrogen,A35110)。
FAK siRNA由吉玛基因提供，序列如下表所示：
F：CCUGUAUGCCUAUCAGCUUTT；
R：AAGCUGAUAGGCAUACAGGTT
实验仪器：
荧光显微镜(Olympus U-HGLGPS)。化学发光成像仪(BIORAD chemidoc touch)
实验结果：
1、FAK沉默后联合Docetaxel显著增加SK-OV-3细胞凋亡
分别使用终浓度为50nM的对照siRNA或FAK siRNA转染SK-OV-3细胞。转染24小时后，分别给予0.3μM或1μM Docetaxel处理48小时，使用Annexin V试剂盒进行细胞染色并使用流式细胞仪进行检测。统计细胞凋亡数值与对照组进行比较并使用Graphpad 8.0进行绘图，结果显示FAK沉默组与对照组比较，经过Docetaxel处理后，凋亡被显著的增强了，如图1所示。
2、FAK沉默后联合Docetaxel显著上调了ICD靶点Calreticulin释放及暴露
分别使用终浓度为50nM的对照siRNA或FAK siRNA转染SK-OV-3细胞。转染24小时后，给予1μM Docetaxel处理48小时，用Calreticulin抗体进行荧光染色，流式细胞仪对染色结果经行分析。FlowJo软件结果统计显示：FAK沉默后联合Docetaxel，Calreticulin的释放及暴露均被显著的增强了，如图2所示。
实施例2：FAK靶点抑制增强乳腺癌细胞针对Eribulin免疫原性细胞死亡的研究
实验方案：
1.FAK沉默，联合Eribulin促进乳腺癌细胞MDA-MB-231凋亡
体外实验利用siRNA技术降低FAK的表达水平，与Eribulin联合使用48小时；利用流式细胞仪，检测对照和FAK沉默的细胞凋亡。
2.FAK沉默，联合Eribulin能够有效促进乳腺癌细胞MDA-MB-231产生ICD作用
体外实验利用siRNA技术降低FAK的表达水，与Eribulin联合使用48小时；利用流式细胞仪，检测ICD的主要靶标Calreticulin的表达情况。
实验抗体：
重组Alexa647荧光Anti-Calreticulin(抗-钙网蛋白)抗体(Abcam，ab196159)，Annexin V细胞凋亡检测试剂盒(Invitrogen,A35110)。
FAK siRNA由吉玛基因提供，序列如下表所示：
F：CCUGUAUGCCUAUCAGCUUTT；
R：AAGCUGAUAGGCAUACAGGTT
实验仪器：
荧光显微镜(Olympus U-HGLGPS)。化学发光成像仪(BIORAD chemidoc touch)。
实验结果：
1、FAK沉默后联合Eribulin显著增加MDA-MB-231细胞凋亡
分别使用终浓度为50nM的对照siRNA或FAK siRNA转染MDA-MB-231细胞。转染24小时后，给予0.15μM Eribulin处理48小时，使用Annexin V试剂盒进行细胞染色并使用流式细胞仪进行检测。统计细胞早期和晚期凋亡数值与DMSO对照组进行比较并使用Graphpad 8.0进行绘图。结果显示FAK沉默组与对照组比较，经过Eribulin处理后，早期及晚期凋亡被显著的增强了，如图3所示。
2、FAK沉默后联合Eribulin显著上调了ICD靶点Calreticulin释放及暴露
分别使用终浓度为50nM的对照siRNA或FAK siRNA转染MDA-MB-231细胞。转染24小时后，给予0.15μM Eribulin处理48小时，用Calreticulin抗体进行荧光染色，流式细胞仪对染色结果经行分析。FlowJo软件结果统计显示：FAK沉默后联合Eribulin，Calreticulin的释放及暴露均被显著的增强了，如图4所示。
实施例3：IN10018和Docetaxel在结肠癌CT26细胞中的协同作用
CT26用RPMI-1640(上海元培，分类号:L210KJ,批号:F210916)+10％FBS(Gibco，分类号:10099-141c,批号:2158737cp)培养，传代两次，当细胞状况良好时，将其放置在96孔板中，3000个细胞/孔。细胞铺展24 小时后，加入含有Docetaxel的培养基，设置10个药物作用浓度，第一个浓度为30μM，3倍稀释，最后一个为对照，药物浓度为0，每个药物浓度设置为3个复合孔。同时，用与上述方法相同的药物浓度建立另一组细胞。不同之处在于，每孔加入5μM IN10018，将药物混合，并在37℃下在5％CO2培养箱中培养72小时。
药物作用72h后，显微镜下观察细胞，向每个孔中加入10μl CCK8检测试剂(Cellorlab，分类号：CX001M，批号：2571100)，在37℃的5％CO2培养箱中培养2-4h，然后用微孔板读取器OD450(化学发光法)读取孔板。分析结果发现，Docetaxel组的IC50为0.19μM；Docetaxel+5μM IN10018组的IC50<0.005μM。含有IN10018的组的IC50显著小于不含IN10018的组，表明两种药物联合治疗组的疗效优于单药治疗组，如图5所示。
实施例4：IN10018和Docetaxel在结肠癌CT26细胞中的研究
CT26细胞(中科院细胞所)用RPMI-1640(上海元培，分类号:L210KJ,批号:F210916)+10％FBS(Gibco，分类号:10099-141c,批号:2158737cp)培养，传代两次，当细胞状况良好时，将培养液放置在24孔板中。细胞铺展24小时后，设四组，第一组为对照组，加入培养基，第二组为IN10018，浓度为5μM，第三组为Docetaxel(MCE，分类号：HY-B0011，批号：111613)，浓度为0.1μM，第四组为IN10018(5μM)和Docetaxel(0.1μM)联用组。将药物混合，并在37℃的5％CO2培养箱中培养48小时。
药物作用48h后，对细胞进行显微镜观察和拍照，并保存照片。然后收集细胞进行流动分析，并用流式缓冲液(PBS+2％FBS)洗涤细胞两次，将0.5μl AF647抗钙网蛋白抗体(abcam，分类号：ab196159，批号：CR33676773)添加到每个孔中，充分混合，在4℃且避光的条件下孵育20min。20min后，用流式缓冲液(PBS+2％FBS)清洗细胞两次。细胞凋亡检测试剂盒(Beyotime，目录号：CL062L，批号：021921210811)，加入195μl膜联蛋白-V-FITC结合物，轻轻混合细胞，加入5μl膜联蛋白-V-FITC抗体，轻轻混合，加入10μl PI染料混合，室温避光培养15min，然后在流式细胞仪上进行分析。
显微镜下观察细胞，Docetaxel单药组和两药联合组细胞状态较差，两药联合组最差，细胞死亡较多，而对照组和IN10018组细胞状态良好。结果显示，双药联合组的CRT阳性率和Annexin V阳性率高于单药组，详见图6， 图7a和图7b。
实施例5：Eribulin和IN10018在小鼠乳腺癌4T1细胞中对免疫原性细胞死亡靶点诱导的研究
化合物信息见表1。
表1：
实验主要试剂信息见表2。
表2：
实验设计见表3。
表3：
细胞培养：
4T1细胞体外单层培养，培养条件为：RPMI-1640培养基中加10％胎牛血清，37℃、5％CO2。一周两到三次用胰蛋白酶进行常规消化传代处理。当细胞处于指数生长期，贴壁汇合至80％-90％时，收取细胞并进行铺板。
4T1细胞用胰蛋白酶进行消化后收取细胞并进行计数，根据计数结果，用RPMI-1640+10％FBS对细胞进行稀释，稀释浓度为5万个细胞每毫升，然后进行12孔细胞培养板铺板，每孔铺2ml细胞悬液即10万个细胞。铺板完成后，将细胞放于37℃、5％CO2培养箱中培养。
加入待测化合物：
铺板24小时后，在不同孔内分别加入待测化合物IN10018和Eribulin，分组及药物浓度如表3所示。
收集细胞进行流式检测：
药物作用48小时后，使用显微镜对细胞进行拍照，然后胰蛋白酶消化细胞并收集细胞进行流式染色。
细胞用流式缓冲液(DPBS+2％FBS)清洗两遍后，每组细胞平均分为两份，其中一份每孔加入0.5μL AF647 Anti-Calreticulin Antibody抗体，混匀后4℃避光孵育20min。此后加入流式缓冲液清洗一遍后加入195μL Annexin-V-FITC结合液，轻轻混匀细胞后加入5μL Annexin-V-FITC抗体，进一步混匀后加入10μL PI染料并进行混匀，室温避光孵育15min后进行流式检测；另一份每孔加入0.5μLGRP94 Polyclonal Antibody，混匀后4℃避光孵育20min，此后加入流式缓冲液清洗两遍后，用200μL流式缓冲液重悬后进行流式检测。
数据分析：
实验结束后，用Flowjo(V10)软件进行细胞阳性率的分析。
实验结果：
各组在药物作用后48小时后，在显微镜下观察细胞状态，Eribulin单药组细胞死亡明显，联合用药组细胞死亡最为显著，对照组和IN10018组细胞活力较好。流式细胞分析结果显示，联合用药组CRT、Annexin-V和GRP94阳性率均明显高于单药组。相关检测结果如图8a、8b和8c所示。
实施例6：Eribulin和IN10018在小鼠卵巢上皮癌ID8细胞和人卵巢上皮癌TOV-21G细胞体外对免疫原性细胞死亡靶点诱导的研究
化合物和主要试剂信息同实施例5。
实验设计见表4。
表4：
细胞培养：
ID8细胞和TOV-21G细胞体外单层培养，ID8细胞培养条件为DMEM培养基中加10％胎牛血清，TOV-21G细胞培养条件为RPMI-1640培养基中加10％胎牛血清，两者均置于37℃、5％CO2培养箱中培养。一周两到三次用胰蛋白酶进行常规消化传代处理。当细胞处于指数生长期，贴壁汇合至80％-90％时，收取细胞并进行铺板。
ID8细胞和TOV-21G细胞用胰蛋白酶进行消化后收取细胞并进行计数，根据计数结果，用对应完全培养基对细胞进行稀释，稀释浓度为5万个细胞每毫升，然后进行12孔细胞培养板铺板，每孔铺2ml细胞悬液即10万个细胞。
铺板完成后，将细胞放于37℃、5％CO2培养箱中培养。
加入待测化合物：
铺板24小时后，在不同孔内分别加入待测化合物IN10018和Eribulin，分组及药物浓度如表4所示。
收集细胞进行流式检测：
药物作用48小时后，使用显微镜对细胞进行拍照，然后胰蛋白酶消化细胞并收集细胞进行流式染色。
细胞用流式缓冲液(DPBS+2％FBS)清洗两遍后，每孔加入0.5μL AF647 Anti-Calreticulin Antibody抗体，混匀后4℃避光孵育20min。此后加入流式 缓冲液清洗一遍后加入195μL Annexin-V-FITC结合液，轻轻混匀细胞后加入5μL Annexin-V-FITC抗体，进一步混匀后加入10μL PI染料并进行混匀，室温避光孵育15min后进行流式检测。
数据分析：
实验结束后，用Flowjo(V10)软件进行细胞阳性率的分析。
实验结果：
在显微镜下观察细胞状态，两个细胞系中均显示：Eribulin单药组细胞死亡明显，联合用药组细胞死亡最为显著，对照组和IN10018组细胞活力较好。流式细胞分析结果显示，联合用药组CRT和Annexin V阳性率均明显高于单药组。ID8细胞系实验结果见图9a和9b；TOV-21G细胞系实验结果见图10a和10b。
实施例7：Docetaxel/Eribulin/Paclitaxel和Defactinib在小鼠结肠癌CT26细胞体外对免疫原性细胞死亡靶点诱导的研究
化合物信息见表5。
表5：
实验主要试剂信息见表2：
实验设计见表6：
表6：

细胞培养：
CT26细胞体外单层培养，细胞培养条件为：RPMI-1640培养基中加10％胎牛血清，37℃、5％CO2。一周两到三次用胰蛋白酶进行常规消化传代处理。当细胞处于指数生长期，贴壁汇合至80％-90％时，收取细胞并进行铺板。
CT26细胞用胰蛋白酶进行消化后收取细胞并进行计数，根据计数结果，用对应完全培养基对细胞进行稀释，稀释浓度为5万个细胞每毫升，然后进行12孔细胞培养板铺板，每孔铺2ml细胞悬液即10万个细胞。
铺板完成后，将细胞放于37℃、5％CO2培养箱中培养。
铺板24H后，在不同孔内分别加入待测化合物Docetaxel、Eribulin、Paclitaxel和Defactinib，分组及药物浓度如表6所示。
药物作用48H后，使用显微镜对细胞进行拍照，然后胰蛋白酶消化细胞并收集细胞进行流式染色。
细胞用流式缓冲液(DPBS+2％FBS)清洗两遍后，每孔加入0.5μL AF647 Anti-Calreticulin Antibody抗体，混匀后4℃避光孵育20min。此后加入流式缓冲液清洗一遍后加入195μL Annexin-V-FITC结合液，轻轻混匀细胞后加入5μL Annexin-V-FITC抗体，进一步混匀后加入10μL PI染料并进行混匀，室温避光孵育15min后进行流式检测。
数据分析：
实验结束后，用Flowjo(V10)软件进行细胞阳性率的分析。
实验结果：
本实验评价了Docetaxel/Eribulin/Paclitaxel单药和分别与Defactinib合用后在体外条件下对CT26细胞诱导表达免疫细胞死亡靶点的作用。
各组在药物作用后48小时后。在显微镜下观察细胞状态，Docetaxel/Eribulin/Paclitaxel单药组细胞死亡明显，联合用药组细胞死亡最为显著，对照组细胞活力较好，Defactinib单药组细胞死亡较为显著。流式细 胞分析结果显示，联合用药组CRT和Annexin V阳性率均明显高于单药组。Docetaxel实验结果见图11a和11b；Eribulin实验结果见图12a和12b；Paclitaxel实验结果见图13a和13b。
实施例8：Docetaxel/Eribulin和Defactinib在小鼠乳腺癌4T1细胞体外对免疫原性细胞死亡靶点诱导的研究
化合物信息见表5(无Paclitaxel)，实验主要试剂信息见表2。
实验设计见表7：
表7：
细胞培养：
4T1细胞体外单层培养，细胞培养条件为RPMI-1640培养基中加10％胎牛血清，置于37℃、5％CO2培养箱中培养。一周两到三次用胰蛋白酶进行常规消化传代处理。当细胞处于指数生长期，贴壁汇合至80％-90％时，收取细胞并进行铺板。
4T1细胞用胰蛋白酶进行消化后收取细胞并进行计数，根据计数结果，用对应完全培养基对细胞进行稀释，稀释浓度为5万个细胞每毫升，然后进行12孔细胞培养板铺板，每孔铺2ml细胞悬液即10万个细胞。
铺板完成后，将细胞放于37℃、5％CO2培养箱中培养。
铺板24小时后，在不同孔内分别加入待测化合物Defactinib、Docetaxel和Eribulin，分组及药物浓度如表7所示。
收集细胞进行流式检测：
药物作用48小时后，使用显微镜对细胞进行拍照，然后胰蛋白酶消化细胞并收集细胞进行流式染色。
细胞用流式缓冲液(DPBS+2％FBS)清洗两遍后，每孔加入0.5μL AF647 Anti-Calreticulin Antibody抗体，混匀后4℃避光孵育20min。此后加入流式缓冲液清洗一遍后加入195μL Annexin-V-FITC结合液，轻轻混匀细胞后加入5μL Annexin-V-FITC抗体，进一步混匀后加入10μL PI染料并进行混匀，室温避光孵育15min后进行流式检测。
数据分析：
实验结束后，用Flowjo(V10)软件进行细胞阳性率的分析。
实验结果：
各组在药物作用后48小时后，在显微镜下观察细胞状态，Docetaxel/Eribulin单药组细胞死亡明显，联合用药组细胞死亡最为显著，对照组细胞活力较好，Defactinib单药组细胞死亡较为显著。流式细胞分析结果显示，联合用药组CRT和Annexin V阳性率均明显高于单药组。Docetaxel实验结果见图14a和14b；Eribulin实验结果见图15a和15b。
实施例9：多西他赛注射液(Docetaxel)在乳腺癌4T1细胞BALB/c小鼠皮下同种移植瘤模型中的体内抗肿瘤药效研究
试验材料：
小鼠：6-8周龄的雌性BALB/c小鼠购自上海斯莱克实验动物有限责任公司。动物到达后在实验环境适应性饲养后开始实验。动物在SPF级动物房以IVC(独立送风系统)笼具饲养(每笼5只)。所有笼具、垫料及饮水在使用前均需灭菌。所有实验人员在动物房操作时应穿着防护服和乳胶手套。笼具、饲料及饮水每周更换两次。饲养环境及光照情况如下：
温度：20-26℃
湿度：40-70％
光照周期：12小时光照，12小时无光照
笼具：以聚碳酸酯制成，体积300mm×180mm×150mm。垫料为玉米芯，每周更换两次。
食物：实验动物在整个实验阶段中可自由进食(辐照灭菌，干颗粒状食物)。
饮水：实验动物可自由饮用灭菌水。
笼具标识：每笼动物信息卡应注明笼内动物数目，性别，品系，接收日 期，给药方案，实验编号，组别以及实验开始日期。
动物标识：实验动物以耳标进行标识。
化合物信息见表8
表8：
乳腺癌细胞4T1(来源南京科佰生物科技有限公司，货号：CBP60352)由应世生物科技(南京)有限公司维持传代。细胞体外单层培养，培养条件为RPMI-1640培养基中加10％胎牛血清，37℃5％CO2培养箱中培养。一周两到三次用胰酶-EDTA进行常规消化处理传代。当细胞处于指数生长期，饱和度为80％-90％时，收取细胞，计数后接种。
细胞接种及分组
将0.1mL含有2×105个细胞的细胞悬液皮下接种于每只小鼠的右后背。当肿瘤体积达到～52mm3时(细胞接种后第10天)，根据肿瘤体积进行随机分组给药，分组信息见表9。
表9.受试物对4T1小鼠移植瘤模型的给药方案
注：1.每组小鼠数目；
2.给药体积：根据小鼠体重10mL/kg，如果体重下降超过15％，动物停止给药；待体重恢复至降低10％，再恢复给药。
受试物的配制详见表10。
表10.
实验动物日常观察
本实验方案的拟定及任何修改均通过了云桥生物IACUC的评估核准。实验动物的使用及福利遵照AAALAC的规定执行。每天监测动物的健康状况及死亡情况，例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动，摄食摄水量(仅目测)，体重变化，外观体征或其它不正 常情况。基于各组动物数量记录了组内动物死亡数和副作用。
实验终止
若动物健康状况持续恶化，或瘤体积超过3000mm3，或有严重疾病，或疼痛，须处以安乐死。有以下情况者，通知兽医并处以安乐死：明显消瘦，体重降低大于20％；不能自由取食和饮水；对照组瘤体积平均值达到2000mm3，实验终止。动物出现以下临床表现且持续恶化：立毛，弓背，耳、鼻、眼或足色发白，呼吸仓促，抽搐，连续腹泻，脱水，行动迟缓，发声。
肿瘤测量和实验指标
用游标卡尺测量肿瘤直径，每周测量3次。肿瘤体积的计算公式为：V＝0.5×a×b2，a和b分别表示肿瘤的长径和短径。
参照分组后第一天的肿瘤体积，根据以下公式计算肿瘤生长抑制率TGI(％)。TGI(％)＝[1-(某给药组的平均瘤体积-该给药组开始治疗时平均瘤体积)/(溶剂对照组的平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100％。
统计分析
统计分析基于试验结束时肿瘤体积运用Prism Graphpad软件进行分析。多组间比较，采用Two-way ANOVA，Fisher’s LSD test法检验进行分析。P<0.05认为有显著性差异。
实验结果
受试物DTX和/或MAX10181与IN10018联用在4T1小鼠乳腺癌细胞BALB/c小鼠皮下同种移植瘤模型中的体内药效。细胞接种后，每天观察肿瘤生长情况，接种后第10天根据肿瘤体积进行分组，入组平均肿瘤体积约为52mm3。由于肿瘤负荷，对照组在接种后的第31天，即分组给药之后的第21天安乐死，整个实验结束。
分组给药后第21天，对照组的肿瘤体积为2129.2±322.0mm3。DTX(10mg/kg)、MAX10181(120mg/kg)、DTX+IN10018(10+25mg/kg)、DTX+MAX10181(10+120mg/kg)和DTX+IN10018+MAX10181(10+25+120mg/kg)各治疗组的肿瘤体积分别为1818.7±644.0mm3，2205.7±912.7mm3，1182.9±264.3mm3，1480.3±345.6mm3和829.4±249.1mm3，详见表11。综合 肿瘤体积与对照组进行比较，DTX(10mg/kg)、MAX10181(120mg/kg)、DTX+IN10018(10+25mg/kg)、DTX+MAX10181(10+120mg/kg)和DTX+IN10018+MAX10181(10+25+120mg/kg)组的抑瘤率TGI分别为14.9％(p＝0.0147)，-3.7％(p＝0.5642)，45.6％(p<0.0001)，31.3％(p<0.0001)和62.6％(p<0.0001),详见表11。综合瘤体积与DTX+IN10018+MAX10181(10+25+120mg/kg)三药联用组相比较，进行统计学分析，对照组、DTX(10mg/kg)、MAX10181(120mg/kg)、DTX+IN10018(10+25mg/kg)和DTX+MAX10181(10+120mg/kg)各组的P值分别为p<0.0001，p<0.0001，p<0.0001，p＝0.0055和p<0.0001。各剂量组在不同时间段的肿瘤体积如图16所示。
表11:基于分组给药后第21天数据
注：1.按照分组给药后的天数来计算，数据为平均值±标准误差。
2.*：p<0.05，****：p<0.0001，vs.对照组，Two-way ANOVA。
3.**：p<0.01，****：p<0.0001，vs.DTX+IN10018+MAX10181(10+25+120mg/kg)组，Two-way ANOVA。
实验按照给药方案进行，实验过程中，每天观察动物摄食饮水等活动，每周记录3次动物体重，动物体重曲线见图17。在整个给药周期中，MAX10181相关组别的动物有出现腹泻的情况，其中导致G3 MAX10181(120mg/kg)和G5DTX+MAX10181(10+120mg/kg)各死亡一只动物。除此之外，DTX+IN10018+MAX10181(10+25+120mg/kg)体重有出现下降，但是没有超过10％；各组组动物精神和运动状态良好，对各种给药方式比较耐受。
结论
与空白对照组相比，DTX(10mg/kg)、DTX+IN10018(10+25mg/kg)、 DTX+MAX10181(10+120mg/kg)和DTX+IN10018+MAX10181(10+25+120mg/kg)治疗组均有明显肿瘤生长抑制作用，和对照组相比都有统计学差异。综合整个给药周期，DTX+IN10018(10+25mg/kg)组的肿瘤体积要小于DTX(10mg/kg)单药组，显示出DTX和IN10018两药联用相对于单药具有更好的药效；DTX+IN10018+MAX10181(10+25+120mg/kg)三药联用组的肿瘤体积相对于各单药组和各两药联用组，且与其余各组相比均有统计学差异，显示出DTX和IN10018以及MAX10181三药联用具有更好的抑制肿瘤生长的效果。虽然MAX10181相关组别给药后会造成动物的腹泻，同时导致了MAX10181(120mg/kg)和DTX+MAX10181(10+120mg/kg)组各死亡一只动物，但是其余动物的精神状况和运动状况良好，说明动物对DTX+IN10018+MAX10181(10+25+120mg/kg)三药联用表现出一定的耐受。
实施例10：多西他赛注射液(Docetaxel)和AMP945对小鼠乳腺癌4T1细胞体外免疫原性细胞死亡靶点诱导的研究
实验材料：
1)本实验所用药物
多西他赛注射液由MCE提供,Lot No.:111613
AMP945由MCE提供,Lot No.:143253
2)本实验所用抗体
重组Alexa647荧光Anti-Calreticulin抗体(Abcam，Cat No.:ab196159,Lot No.:CR33676773)。Annexin V-调亡检测试剂盒(Beyotime,Cat No.:C1062L,Lot No.:122221220706)。
实验方法：
4T1细胞(来源南京科佰生物科技有限公司，货号：CBP60352)用RPMI-1640(上海元培,Cat No.:L210KJ,Lot No.:F210916)+10％FBS(Gibco,Cat No.:10099-141c,Lot No.:2158737cp)培养，培养条件为37℃、5％CO2。一周两到三次用胰蛋白酶进行常规消化传代处理。当细胞处于指数生长期，贴壁汇合至80％-90％时，收取细胞并进行铺板。4T1细胞用胰蛋白酶进行消化后收取细胞并进行计数，根据计数结果，用RPMI-1640+10％FBS对细胞进行稀释，稀释浓度为5万个细胞每毫升，然后进行12孔细胞培养板铺板， 每孔铺2ml细胞悬液即10万个细胞。铺板完成后，将细胞放于37℃、5％CO2培养箱中培养。细胞铺展24小时后，设立六组，第一组为对照组，添加培养基，第二组为AMP945，浓度为3μM，第三组为AMP945，浓度为6μM，第四组为多西他赛注射液(Docetaxel)，浓度为0.3μM，第五组为AMP945(3μM)与Docetaxel(0.3μM)联用，第六组为AMP945(6μM)与Docetaxel(0.3μM)联用。将药物混合，并在37℃下在5％CO2培养箱中培养48小时。
实验结果
药物作用48h后，收集细胞进行流动分析，并使用流式缓冲液(PBS+2％FBS)清洗细胞两次，每个孔中加入0.5μl AF647抗钙网蛋白抗体(abcam)，混合。在4℃且避光的条件下孵育，孵育20min后加入流式缓冲液，使用膜联蛋白染色试剂盒(Beyotime)，加入195μl Annexin-V-FITC结合液，与细胞进行吹打混合后，加入5μl Annexin-V-FITC抗体，轻轻混合，最后加入10μl PI染料混合，室温避光孵育15min，将样品送至流式细胞仪上进行信号测定。
流式细胞仪分析结果显示两药合用组的CRT阳性率和Annexin-V阳性率显著优于单药组及对照组，见图18a和18b。
实施例11：Eribulin和AMP945对小鼠乳腺癌4T1细胞体外免疫原性细胞死亡靶点诱导的研究
实验材料：
1)本实验所用药物
Eribulin由北京桦冠医药科技有限公司提供,Lot No.:HG-000000011-000-001
AMP945由MCE提供,Lot No.:143253
2)本实验所用抗体
重组Alexa647荧光Anti-Calreticulin抗体(Abcam，Cat No.:ab196159,Lot No.:CR33676773)。Annexin V-调亡检测试剂盒(Beyotime,Cat No.:C1062L,Lot No.:122221220706)。
实验方法：
4T1细胞(来源南京科佰生物科技有限公司，货号：CBP60352)用RPMI1640(上海元培,Cat No.:L210KJ,Lot No.:F210916)+10％FBS(Gibco,Cat No.:10099-141c,Lot No.:2158737cp)培养，培养条件为37℃、5％CO2。一周两到三次用胰蛋白酶进行常规消化传代处理。当细胞处于指数生长期，贴壁汇合至80％-90％时，收取细胞并进行铺板。4T1细胞用胰蛋白酶进行消化后收取细胞并进行计数，根据计数结果，用RPMI-1640+10％FBS对细胞进行稀释，稀释浓度为5万个细胞每毫升，然后进行12孔细胞培养板铺板，每孔铺2ml细胞悬液即10万个细胞。铺板完成后，将细胞放于37℃、5％CO2培养箱中培养。细胞铺展24小时后，设立六组，第一组为对照组，添加培养基，第二组为AMP945，浓度为3μM，第三组为AMP945，浓度为6μM，第四组为Eribulin，浓度为0.3μM，第五组为AMP945(3μM)与Eribulin(0.3μM)联用，第六组为AMP945(6μM)与Eribulin(0.3μM)联用。将药物混合，并在37℃下在5％CO2培养箱中培养48小时。
实验结果
药物作用48h后，收集细胞进行流动分析，并使用流式缓冲液(PBS+2％FBS)清洗细胞两次，每个孔中加入0.5μl AF647抗钙网蛋白抗体(abcam)，混合。在4℃且避光的条件下孵育，孵育20min后加入流式缓冲液，使用膜联蛋白染色试剂盒(Beyotime)，加入195μl Annexin-V-FITC结合液，与细胞进行吹打混合后，加入5μl Annexin-V-FITC抗体，轻轻混合，最后加入10μl PI染料混合，室温避光孵育15min，将样品送至流式细胞仪上进行信号测定。
流式细胞仪分析结果显示两药合用组的CRT阳性率和Annexin-V阳性率显著优于单药组及对照组，见图19a和19b。
通过引用将本发明中所提及的所有参考文献均完整合并入本文，就如同每一篇文献均单独列出一样。应理解，在阅读了本发明的公开内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落入本申请所附权利要求书所限定的范围内。

Claims (43)

  1. FAK抑制剂、微管抑制剂和免疫检查点抑制剂在制备用于在对象中治疗肿瘤的药物中的用途。
  2. FAK抑制剂、微管抑制剂和免疫检查点抑制剂的药物组合产品，其用于在对象中治疗肿瘤。
  3. 一种治疗肿瘤的方法，该方法包括向对象施用治疗有效量的FAK抑制剂、微管抑制剂和免疫检查点抑制剂。
  4. 如权利要求1-3任一项所述的用途、药物组合产品或者方法，其中所述FAK抑制剂和所述微管抑制剂诱导免疫原性细胞死亡(ICD)。
  5. 如权利要求1-4任一项所述的用途、药物组合产品或者方法，其中所述FAK抑制剂为IN10018、Defactinib、GSK2256098、PF-00562271、VS-4718、APG-2449、AMP945、AMP886或其药学上可接受的盐，优选为IN10018、Defactinib、AMP945、或其药学上可接受的盐，进一步优选为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐，所述IN10018结构如下：
  6. 如权利要求1-5任一项所述的用途、药物组合产品或者方法，其中所述微管抑制剂为紫杉类药物、艾瑞布林(Eribulin)、伊沙匹隆(Ixempra)或长春花生物碱。
  7. 如权利要求1-6任一项所述的用途、药物组合产品或者方法，其中所述微管抑制剂为紫杉类药物。
  8. 如权利要求6-7任一项所述的用途、药物组合产品或者方法，其中所述紫杉类药物为多西他赛(Docetaxel)、紫衫醇(Paclitaxel)、卡巴他赛(Cabazitaxel)或三尖杉宁碱(Cephalomannine)，优选为多西他赛(Docetaxel)或紫衫醇(Paclitaxel)。
  9. 如权利要求1-8任一项所述的用途、药物组合产品或者方法，其中所述微管抑制剂为多西他赛(Docetaxel)。
  10. 如权利要求1-8任一项所述的用途、药物组合产品或者方法，其中所述微管抑制剂为紫衫醇(Paclitaxel)。
  11. 如权利要求1-6任一项所述的用途、药物组合产品或者方法，其中所述微管抑制剂为艾瑞布林(Eribulin)。
  12. 如权利要求1-11任一项所述的用途、药物组合产品或者方法，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体、PD-1/PD-L1小分子抑制剂或者TIGIT抑制剂。
  13. 如权利要求1-12任一项所述的用途、药物组合产品或者方法，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，进一步的，所述抗PD-1/PD-L1抗体为帕博利珠单抗(pembrolizumab)、替雷利珠单抗(Tislelizumab)、尼伏单抗(Nivolumab)、特瑞普利单抗(Toripalimab)、阿替利珠单抗(Atezolizumab)、度伐单抗(durvalumab)、阿维单抗(Avelumab)、卡瑞利珠单抗(Camrelizumab)、信迪利单抗(Sintilimab)、西米普利单抗(Cemiplimab)、恩沃利单抗(envafolimab)、BMS-936559、JS003、SHR-1316、GS-4224、AN-4005或者MX-10181。
  14. 如权利要求1-12任一项所述的用途、药物组合产品或者方法，其中所述免疫检查点抑制剂为PD-1/PD-L1小分子抑制剂，进一步的，所述PD-1/PD-L1小分子抑制剂为INCB-086550、拉泽替尼(Lazertinib)、IMMH-010、CA-170、ABSK043或者RRx-001。
  15. 如权利要求1-12任一项所述的用途、药物组合产品或者方法，其中所述免疫检查点抑制剂为TIGIT抑制剂，进一步的，所述TIGIT抑制剂为欧司珀利单抗(Ociperlimab/BGB-A1217)、维博利单抗(Vibostolimab)、domvanalimab(AB154)、替瑞利尤单抗(Tiragolumab)、Belrestotug、艾替利单抗(Etigilimab)、ONO-4686、JS-006、AZD-2936、HLX-301、SEA-TGT、M-6223、IBI-939、COM-902、AB-308、AGEN-1777、AK-127、BAT-6021、BAT-6005、ASP-8374、PM-1022、BMS-986207、HB0036或IBI-321。
  16. 如权利要求1-4任一项所述的用途、药物组合产品或者方法，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为 抗PD-1/PD-L1抗体。
  17. 如权利要求1-4任一项所述的用途、药物组合产品或者方法，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
  18. 如权利要求1-17任一项所述的用途、药物组合产品或者方法，所述FAK抑制剂、所述微管抑制剂和所述免疫检查点抑制剂被同时或依次施用于所述对象。
  19. 如权利要求1-18任一项所述的用途、药物组合产品或者方法，其中所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选地，所述肿瘤为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌。
  20. 如权利要求1-19任一项所述的用途、药物组合产品或者方法，其中所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
  21. 一种试剂盒或药学上可接受的组合物，其包括：
    (a)FAK抑制剂；
    (b)微管抑制剂；和
    (c)免疫检查点抑制剂。
  22. 如权利要求21所述的试剂盒或组合物，其中所述FAK抑制剂和所述微管抑制剂诱导免疫原性细胞死亡(ICD)。
  23. 如权利要求21-22任一项所述的试剂盒或组合物，其中所述FAK抑制剂为IN10018、Defactinib、GSK2256098、PF-00562271、VS-4718、APG-2449、AMP945、AMP886或其药学上可接受的盐，优选为IN10018、Defactinib、AMP945、或其药学上可接受的盐，进一步优选为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐，所述IN10018结构如下：
  24. 如权利要求21-23任一项所述的试剂盒或组合物，其中所述微管抑制剂为紫杉类药物、艾瑞布林(Eribulin)、伊沙匹隆(Ixempra)或长春花生物碱。
  25. 如权利要求21-24任一项所述的试剂盒或组合物，其中所述微管抑制剂为紫杉类药物。
  26. 如权利要求24-25任一项所述的试剂盒或组合物，其中所述紫杉类药物为多西他赛(Docetaxel)、紫衫醇(Paclitaxel)、卡巴他赛(Cabazitaxel)或三尖杉宁碱(Cephalomannine)，优选为多西他赛(Docetaxel)或紫衫醇(Paclitaxel)。
  27. 如权利要求21-26任一项所述的试剂盒或组合物，其中所述微管抑制剂为多西他赛(Docetaxel)。
  28. 如权利要求21-26任一项所述的试剂盒或组合物，其中所述微管抑制剂为紫衫醇(Paclitaxel)。
  29. 如权利要求21-24任一项所述的试剂盒或组合物，其中所述微管抑制剂为艾瑞布林(Eribulin)。
  30. 如权利要求21-29任一项所述的试剂盒或组合物，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体、PD-1/PD-L1小分子抑制剂或者TIGIT抑制剂。
  31. 如权利要求21-30任一项所述的试剂盒或组合物，其中所述免疫检查点抑制剂为抗PD-1/PD-L1抗体，进一步的，所述抗PD-1/PD-L1抗体为帕博利珠单抗(pembrolizumab)、替雷利珠单抗(Tislelizumab)、尼伏单抗(Nivolumab)、特瑞普利单抗(Toripalimab)、阿替利珠单抗(Atezolizumab)、度伐单抗(durvalumab)、阿维单抗(Avelumab)、卡瑞利珠单抗(Camrelizumab)、 信迪利单抗(Sintilimab)、西米普利单抗(Cemiplimab)、恩沃利单抗(envafolimab)、BMS-936559、JS003、SHR-1316、GS-4224、AN-4005或者MX-10181。
  32. 如权利要求21-30任一项所述的试剂盒或组合物，其中所述免疫检查点抑制剂为PD-1/PD-L1小分子抑制剂，进一步的，所述PD-1/PD-L1小分子抑制剂为INCB-086550、拉泽替尼(Lazertinib)、IMMH-010、CA-170、ABSK043或者RRx-001。
  33. 如权利要求21-30任一项所述的试剂盒或组合物，其中所述免疫检查点抑制剂为TIGIT抑制剂，进一步的，所述TIGIT抑制剂为欧司珀利单抗(Ociperlimab/BGB-A1217)、维博利单抗(Vibostolimab)、domvanalimab(AB154)、替瑞利尤单抗(Tiragolumab)、Belrestotug、艾替利单抗(Etigilimab)、ONO-4686、JS-006、AZD-2936、HLX-301、SEA-TGT、M-6223、IBI-939、COM-902、AB-308、AGEN-1777、AK-127、BAT-6021、BAT-6005、ASP-8374、PM-1022、BMS-986207、HB0036或IBI-321。
  34. 如权利要求21-22任一项所述的试剂盒或组合物，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为多西他赛(Docetaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
  35. 如权利要求21-22任一项所述的试剂盒或组合物，其中所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体或PD-1/PD-L1小分子抑制剂，尤其是所述FAK抑制剂为IN10018或其药学上可接受的盐，所述微管抑制剂为紫衫醇(Paclitaxel)；所述免疫检查点抑制剂为抗PD-1/PD-L1抗体。
  36. 如权利要求21-35任一项所述的试剂盒或组合物，其用作药物。
  37. 如权利要求21-36任一项所述的试剂盒或组合物，其中所述药物用于治疗肿瘤，所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成 神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选地，所述肿瘤为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌。
  38. 如权利要求37所述的试剂盒或组合物，其中所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
  39. FAK抑制剂，其在治疗肿瘤中用于增强微管抑制剂诱导的免疫原性细胞死亡。
  40. 如权利要求39所述的FAK抑制剂，其中所述FAK抑制剂为IN10018、Defactinib、GSK2256098、PF-00562271、VS-4718、APG-2449、AMP945、AMP886或其药学上可接受的盐，优选为IN10018、Defactinib、AMP945、或其药学上可接受的盐，进一步优选为IN10018或其药学上可接受的盐，尤其是IN10018酒石酸盐，所述IN10018结构如下：
  41. 如权利要求39或40所述的FAK抑制剂，其中所述微管抑制剂为紫杉类药物、艾瑞布林(Eribulin)、伊沙匹隆(Ixempra)或长春花生物碱。
  42. 如权利要求41所述的FAK抑制剂，其中所述紫杉类药物为多西他赛(Docetaxel)、紫衫醇(Paclitaxel)、卡巴他赛(Cabazitaxel)或三尖杉宁碱(Cephalomannine)，优选为多西他赛(Docetaxel)或紫衫醇(Paclitaxel)。
  43. 如权利要求39-42任一项所述的FAK抑制剂，所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、 横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤或者恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选地，所述肿瘤为乳腺癌、卵巢癌、结肠癌(包括结直肠癌)、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤或胰腺癌；更优选地，所述肿瘤为乳腺癌、卵巢癌或结肠癌(包括结直肠癌)。
PCT/CN2023/114225 2022-08-24 2023-08-22 Fak抑制剂及微管抑制剂的药物组合及用途 WO2024041527A1 (zh)

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CN114667144A (zh) * 2019-11-18 2022-06-24 应世生物科技(南京)有限公司 Fak抑制剂在制备用于治疗nras突变的肿瘤的药物中的用途
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