Joint use of FAK inhibitor and KRAS g12c inhibitor

Abstract

The present invention relates to the use of a FAK inhibitor in preparing a drug to be jointly used with a KRAS G12C inhibitor to treat a tumor.

Description

Combination of FAK inhibitors and KRAS G12C inhibitors Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to the use of a FAK inhibitor in the preparation of a drug for treating tumors in combination with a KRAS G12C inhibitor. Background Art

[0002] KRAS is the oncogene with the highest mutation frequency during cancer development, and its mutations mainly occur in cancers such as lung cancer, pancreatic cancer, and colorectal cancer. KRAS was discovered in the early 1980s, but it was not until 2013 that the first targeting pocket of the KRAS G12C mutation was discovered, which keeps KRAS in an inactive state to inhibit KRAS activity and thus produce an anti-tumor effect. Based on this principle, a variety of KRAS G12C inhibitors have been developed, among which Sotorasib (also known as AMG510) has been marketed and is mainly used for the treatment of non-small cell lung cancer. However, the above-mentioned KRAS G12C inhibitors are first-generation targeted inhibitors and have the potential problem of limited efficacy. Therefore, there is still a need to explore new methods for treating cancer, especially tumors with KRAS mutations. Summary of the Invention

[0003] The applicants discovered that a key mechanism of resistance to KRAS G12C inhibitors is the feedback upregulation of the FAK-YAP signaling pathway, leading to evasion of the targeted apoptotic response. The combination of AMG510 and FAK inhibitors produces a strong synergistic anti-tumor response. Through exploration, the applicants discovered the synergistic effect of second-generation KRAS G12C inhibitors and FAK inhibitors. This combination regimen will further enhance the synergistic effect of first-generation AMG510 and FAK inhibitors, benefiting cancer patients, particularly those with KRAS G12C mutations.

[0004] In one aspect, the present invention provides a use of a FAK inhibitor in the preparation of a medicament for treating tumors in combination with a KRAS G12C inhibitor, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

[0005] In another aspect, the present invention provides use of a FAK inhibitor and a KRAS G12C inhibitor in the preparation of a medicament for treating tumors, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

[0006] On the other hand, the present invention provides a FAK inhibitor and a KRAS G12C inhibitor for treating tumors, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

[0007] In another aspect, the present invention provides a method for treating tumors, comprising administering a FAK inhibitor and a KRAS G12C inhibitor to a subject, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, in particular a therapeutically effective amount of a FAK inhibitor and a therapeutically effective amount of a KRAS G12C inhibitor.

[0008] In another aspect, the present invention provides a pharmaceutical combination product comprising:

[0009] (a) FAK inhibitors, and

[0010] (b) KRAS G12C inhibitors,

[0011] The FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

[0012] Optionally, the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, deuterated compound 1 of Defactinib (CAS No. 2384121-03-1), deuterated compound 2 of Defactinib (CAS No. 2384120-99-2), or a pharmaceutically acceptable salt thereof.

[0013] Optionally, the FAK inhibitor is a deuterated compound of Defactinib, AMP945, APG-2449 or Conteltinib.

[0014] Optionally, the FAK inhibitor and the KRAS G12C inhibitor are administered simultaneously, separately or sequentially.

[0015] Optionally, the FAK inhibitor is administered at a dose of about 25 mg / day to 1000 mg / day. Further, the FAK inhibitor is administered at a dose of about 25 mg / day to 500 mg / day.

[0016] Optionally, the KRAS G12C inhibitor is administered at a dose of about 100 mg / day to 2000 mg / day.

[0017] Optionally, the tumor is a tumor with a KRAS mutation, further a tumor with a KRAS G12C mutation.

[0018] Optionally, the tumor is lung adenocarcinoma, non-small cell lung cancer, colorectal cancer (CRC) (including colon cancer and rectal cancer), endometrial cancer, bladder urothelial carcinoma, invasive lobular carcinoma of the breast, cervical squamous cell carcinoma, skin melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic cancer, biphasic pleural mesothelioma, renal clear cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinosarcoma, or uterine malignant mixed Mullerian tumor.

[0019] Optionally, the tumor is non-small cell lung cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 depicts the effects of different concentrations of a KRAS G12C inhibitor combined with AMP945 on the proliferation of NCI-H2122 cells. Three different drug concentrations of the KRAS G12C inhibitor were selected: 10 μM, 2 μM, and 0.4 μM. A fixed concentration of AMP945, 1 / 4 of the IC50, was selected.

[0021] Figure 2 depicts the effects of different concentrations of a KRAS G12C inhibitor combined with Defactinib on the proliferation of NCI-H2122 cells. Three different drug concentrations of the KRAS G12C inhibitor were selected: 10 μM, 2 μM, and 0.4 μM. A fixed concentration of 1 / 4 IC50 was selected for Defactinib.

[0022] Figure 3 depicts the effects of different concentrations of a KRAS G12C inhibitor combined with AMP945 on the proliferation of NCI-H358 cells. Three different drug concentrations of the KRAS G12C inhibitor were selected: 10 μM, 0.016 μM, and 0.0032 μM. A fixed concentration of AMP945, 1 / 4 of the IC50, was selected.

[0023] Figure 4 depicts the effects of different concentrations of a KRAS G12C inhibitor combined with Defactinib on the proliferation of NCI-H358 cells. Three different drug concentrations of the KRAS G12C inhibitor were selected: 10 μM, 0.016 μM, and 0.0032 μM. A fixed concentration of 1 / 4 IC50 was selected for Defactinib.

[0024] FIG5 depicts the effects of different concentrations of KRAS G12C inhibitors on the proliferation of NCI-H2122 cells.

[0025] Figure 6 depicts the effects of different concentrations of KRAS G12C inhibitors combined with APG-2449 on the proliferation of NCI-H2122 cells. The APG-2449 concentration was 1 / 4 of the IC50, and the IC50 of APG-2449 was 3.5 μM.

[0026] Figure 7 depicts the effects of different concentrations of KRAS G12C inhibitors combined with Conteltinib on the proliferation of NCI-H2122 cells. The Conteltinib concentration was 1 / 4 of the IC50, and the IC50 of Conteltinib was 7 μM. DETAILED DESCRIPTION

[0027] To make the purpose, technical solutions, and advantages of the embodiments of the present disclosure more clear, the technical solutions of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the drawings of the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, not all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] The present invention may be implemented in other specific forms without departing from the essential attributes of the present invention. It should be understood that, without conflict, any and all embodiments of the present invention may be combined with the technical features of any other embodiment or multiple other embodiments to produce additional embodiments. The present invention includes additional embodiments resulting from such combinations.

[0029] All publications and patents mentioned in this disclosure are hereby incorporated into the present disclosure in their entirety by reference. If the purposes or terms used in any publications and patents incorporated by reference conflict with the purposes or terms used in this disclosure, then the purposes and terms of this disclosure shall prevail.

[0030] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0031] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly used in the art to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0032] Except in the working examples, or where otherwise indicated, all numbers stating quantitative properties, such as dosages, in the specification and claims are to be understood as modified in all instances by the term "about." "About" and "approximately" generally mean an acceptable degree of error in the amount measured, taking into account the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values. It is also to be understood that any numerical range recited herein is intended to include all subranges within that range and any combination of the individual endpoints of that range or subrange. For example, the KRAS The G12C inhibitor is administered at a dosage of about 100 mg / day to about 2000 mg / day, for example, about 100 mg / day to about 1500 mg / day, about 100 mg / day to about 1000 mg / day, about 100 mg / day to about 800 mg / day, about 100 mg / day to about 600 mg / day, about 100 mg / day to about 400 mg / day, about 100 mg / day to about 200 mg / day, about 200 mg / day to about 2000 mg / day, about 200 mg / day to about 1500 mg / day, about 200 mg / day to about 1000 mg / day, about 200 mg / day to about 800 mg / day, about 200 mg / day to about 600 mg / day, about 200 mg / day to about 400 mg / day, about 400 mg / day to about 2000 mg / day. / day, about 400 mg / day to about 1500 mg / day, about 400 mg / day to about 1000 mg / day, about 400 mg / day to about 800 mg / day, about 400 mg / day to about 600 mg / day, about 600 mg / day to about 2000 mg / day, about 600 mg / day to about 1500 mg / day, about 600 mg / day to about 1000 mg / day, about 600 mg / day to about 800 mg / day, about 800 mg / day to about 2000 mg / day, 800 mg / day to about 1500 mg / day, about 800 mg / day to about 1000 mg / day, about 900 mg / day to about 2000 mg / day, about 900 mg / day to about 1500 mg / day, about 900 mg / day to about 1000 mg / day. In some embodiments, the KRAS G12C inhibitor is administered at about 100 mg / day. In some embodiments, the KRAS G12C inhibitor is administered at about 200 mg / day. In some embodiments, the KRAS G12C inhibitor is administered at about 300 mg / day. In some embodiments, the KRAS G12C inhibitor is administered at about 400 mg / day. In some embodiments, the KRAS G12C inhibitor is administered at about 500 mg / day. In some embodiments, the KRAS G12C inhibitor is administered at about 600 mg / day. In some embodiments, the KRAS G12C inhibitor is administered at about 700 mg / day.In some embodiments, the KRAS G12C inhibitor is administered at about 800 mg / day. In some embodiments, the KRAS G12C inhibitor is administered at about 900 mg / day. In some embodiments, the KRAS G12C inhibitor is administered at about 1000 mg / day.

[0033] As used in this disclosure, words such as "include," "comprising," or "including" mean that the elements preceding the word include the elements listed after the word and their equivalents, without excluding unlisted elements. The terms "comprising" or "including" as used herein may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0034] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources.

[0035] The present invention relates to use of a FAK inhibitor in preparing a medicament for treating tumors in combination with a KRAS G12C inhibitor, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

[0036] The present invention also relates to the use of a FAK inhibitor and a KRAS G12C inhibitor in the preparation of a medicament for treating tumors, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

[0037] The present invention also relates to a FAK inhibitor and a KRAS G12C inhibitor, which are used to treat tumors, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

[0038] The present invention also relates to a method for treating tumors, comprising administering a FAK inhibitor and a KRAS G12C inhibitor to a subject, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof, in particular a therapeutically effective amount of a FAK inhibitor and a therapeutically effective amount of a KRAS G12C inhibitor.

[0039] The present invention also relates to a pharmaceutical combination product comprising: (a) a FAK inhibitor, and (b) a KRAS G12C inhibitor, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, deuterated compound 1 of Defactinib (CAS No. 2384121-03-1), deuterated compound 2 of Defactinib (CAS No. 2384120-99-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the FAK inhibitor is a deuterated compound of Defactinib, AMP945, APG-2449 or Conteltinib.

[0041] FAK inhibitors, effective inhibitors of FAK protein tyrosine kinases, can be used in mammals, particularly humans, as antiproliferative agents (e.g., anticancer agents), antitumor agents (e.g., effective against solid tumors), antiangiogenic agents (e.g., stopping or preventing blood vessel proliferation). The compounds described herein, such as FAK inhibitors, can be used to prevent and treat the diseases or conditions described herein (e.g., cancer). The compounds described herein, such as FAK inhibitors, can be used to prevent and treat non-hematological malignancies, various human hyperproliferative diseases, such as the following malignant and benign tumors: liver, kidney, bladder, breast, stomach, ovary, colorectal cancer, prostate cancer, pancreatic cancer, lung cancer, vulvar cancer, thyroid cancer, liver cancer, sarcoma, glioblastoma, head and neck cancer and other proliferative diseases, such as benign skin hyperplasia (e.g., psoriasis) and benign prostatic hyperplasia (e.g., BPH), as well as to prevent and treat diseases such as mesothelioma.

[0042] Defactinib, which has the following structure: It is also known as VS-6063 (e.g., VS-6063 free base) or PF-04554878. VS-6063 and related compounds are also disclosed, for example, in U.S. Patent No. 7,928,109, the contents of which are incorporated herein by reference. In some embodiments, VS-6063 can form a pharmaceutically acceptable salt (e.g., a hydrochloride salt),

[0043] Defactinib has multiple deuterated compounds, such as deuterated compound 1 of Defactinib (CAS No. 2384121-03-1) and deuterated compound 2 of Defactinib (CAS No. 2384120-99-2).

[0044] AMP945 has the following structure, and its synthesis and characterization are described in WO2012110773. In some embodiments, AMP945 can form a pharmaceutically acceptable salt (e.g., tartrate).

[0045] The CAS NO of APG-2449 is 2196186-84-0.

[0046] Conteltinib, also known as CT-707, has a CAS NO of 1384860-29-0.

[0047] Exemplary KRAS G12C inhibitors are as follows:

[0048] RMC-4998, whose CAS No is 2642037-07-6;

[0049] Divarasib, whose CAS No is 2417987-45-0;

[0050] LY3537982, whose CAS No is 2414198-64-2;

[0051] Opnurasib, whose CAS No is 2653994-08-0;

[0052] AMG510, its CAS No. is 2296729-00-3.

[0053] As used herein, "combination use," "combination therapy," and "drug combination" refer to the use of a drug in combination with one or more other drugs to treat a disease, including both the combination of a drug with one or more other drugs and the combination of a drug with instructions indicating that the drug can be used in combination with one or more other drugs.

[0054] As used herein, "drug combination" or "drug combination product" may refer to a fixed combination in the form of one dosage unit (for example, all active pharmaceutical ingredients are present in one dosage form) or a kit of parts for combined administration, or it may refer to a combination of one drug and instructions indicating that the drug can be used in combination with one or more other drugs.

[0055] "Simultaneous, alternating, or sequential" as used herein refers to the simultaneous administration of two or more drugs within a dosing cycle (e.g., within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours) or sequential administration at certain time intervals. The modes of drug administration (e.g., oral, intravenous, intramuscular, or subcutaneous administration, etc.) may be the same or different, and the dosing frequency / cycle of the two or more drugs may be the same or different. When the methods, products, or uses disclosed herein involve two drugs, the two drugs may be administered simultaneously or separately at certain time intervals.

[0056] As used herein, the term "treat" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partial or substantial achievement of one or more of the following: partial or complete alleviation of the extent of a disease, condition, or syndrome; improvement of clinical symptoms or indicators associated with the disease; or delaying, inhibiting, or reducing the likelihood of progression of a disease, condition, or syndrome.

[0057] As used herein, the term "tumor" refers to an abnormal lesion formed when cells in local tissues lose normal genetic regulation of their growth under the influence of various tumorigenic factors, resulting in abnormal proliferation of clonal types. Examples of tumors include, but are not limited to, lung adenocarcinoma, non-small cell lung cancer, colorectal cancer (CRC) (including colon cancer and rectal cancer), endometrial cancer, urothelial carcinoma of the bladder, invasive lobular carcinoma of the breast, cervical squamous cell carcinoma, skin melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic cancer, biphasic pleural mesothelioma, renal clear cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinosarcoma, or malignant mixed Mullerian tumor of the uterus.

[0058] As used herein, the term "pharmaceutically acceptable" means non-toxic, biologically tolerable, and suitable for administration to a subject.

[0059] The term "pharmaceutically acceptable salt" as used herein refers to a non-toxic, biologically tolerable salt suitable for administration to a subject. For example, a pharmaceutically acceptable salt of a compound of formula (I) refers to a non-toxic, biologically tolerable acid addition salt suitable for administration to a subject, including but not limited to: an acid addition salt formed by the compound with an inorganic acid, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and an acid addition salt formed by the compound with an organic acid, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate and an acid addition salt with the formula HOOC-(CH2) n -COOH (wherein n is 0-4) formed by alkanedicarboxylic acid salts, etc. Pharmaceutically acceptable salts can be obtained by conventional methods well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid that provides a physiologically acceptable anion. In some embodiments, the pharmaceutically acceptable salt is tartrate.

[0060] As used herein, the term "patient" or "subject" refers to both mammals and non-mammals. Mammals refer to any member of the class mammalia, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds. The term "subject" does not limit the subject to a particular age or sex. In some embodiments, the subject is a human.

[0061] As used herein, the term "effective amount" refers to an amount of a FAK inhibitor or KRAS G12C inhibitor sufficient to reduce or ameliorate the severity, duration, or onset of a disease or condition, delay or arrest the progression of a disease or condition, cause regression of a disease or condition, or delay the recurrence or progression of symptoms, or enhance or improve the therapeutic effect of another therapy. The precise amount of a FAK inhibitor or KRAS G12C inhibitor administered to a subject will depend on various factors, such as the specific drug or compound, the drug formulation, the route of administration, the type of disease, the condition, the identity of the subject or host being treated, etc., but can be routinely determined by one skilled in the art. For example, determining an effective amount also depends on the extent, severity, and type of cell proliferation. A skilled artisan will be able to determine an appropriate dosage based on these and other factors. When co-administered with other therapeutic agents, for example, when co-administered with an anticancer agent, the "effective amount" of any other therapeutic agent will depend on the type of drug used. Appropriate dosages are known for approved therapeutics and can be adjusted by a skilled artisan based on the subject's condition, the type of condition being treated, and the amount of the compound or a pharmaceutically acceptable salt thereof. Where no quantity is explicitly stated, some quantity should be assumed.

[0062] The effective dose of the FAK inhibitor may be, for example, 10 mg to 2000 mg / day. In some embodiments, the effective dose of the FAK inhibitor may be, for example, 25 mg to 1000 mg / day; in some embodiments, the effective dose of the FAK inhibitor may be, for example, 25 mg to 500 mg / day.

[0063] The effective dose of the KRAS G12C inhibitor can be, for example, 10 mg to 2000 mg / day. In some embodiments, the effective dose of the KRAS G12C inhibitor can be, for example, 25 mg to 1000 mg / day; in some embodiments, the effective dose of the KRAS G12C inhibitor can be, for example, 100 mg to 2000 mg / day.

[0064] The dosage and administration regimen of the FAK inhibitor or KRAS G12C inhibitor required for treatment may vary not only with the specific salt selected, but also with the route of administration, the nature of the disease being treated, the age and physical condition of the patient, and whether there are concurrent chronic diseases of other organs, and can ultimately be determined at the discretion of the attending physician or clinician.

[0065] Example

[0066] The following examples are provided to further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0067] The experimental methods in the following examples without specifying specific conditions can be carried out according to the conventional conditions of such experiments or the conditions recommended by the manufacturer.

[0068] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources.

[0069] Example 1: Study on the inhibitory activity of KRAS G12C inhibitor combined with three different FAK inhibitors on cell proliferation in vitro.

[0070] NCI-H2122 / NCI-H358 (non-small cell lung cancer cell line) cells were revived and maintained by Inspiron Biotech (Nanjing) Co., Ltd. Cells were cultured as adherent monolayers in RPMI1640 medium supplemented with 10% fetal bovine serum at 37°C and 5% CO2. Cells were trypsinized and passaged two to three times weekly. When cells reached 80%-90% confluence during the exponential growth phase, they were harvested and plated.

[0071] NCI-H2122 / NCI-H358 cells were trypsinized, harvested, and counted. Based on the count, the cells were diluted to 30,000 cells / mL using the appropriate culture medium. The cells were then plated into 96-well flat-bottom culture plates, with 0.1 mL of cell suspension added to each well, equating to 3,000 cells. After plating, the plates were placed in a 37°C, 5% CO2 incubator for continued culture.

[0072] 24 hours after cell plating, test compounds were added to different wells of the cell plate. Grouping is shown in Tables 1 and 2, and test compound information is shown in Table 3. After drug addition, the drugs were gently mixed, and the cells were then cultured in a 37°C, 5% CO2 incubator.

[0073] Table 1: Grouping scheme for NCI-H2122 cell proliferation inhibition assay

[0074] Previously, the IC50 values ​​of AMP945 and Defactinib were determined to be 6.2 μM and 6.9 μM, respectively, in CT26 cells. Therefore, the 1 / 4 IC50 values ​​for AMP945 and Defactinib in this experiment were 1.55 μM and 1 / 4 IC50 values ​​for Defactinib, respectively, were 1.72 μM.

[0075] Table 2: Grouping scheme for NCI-H358 cell proliferation inhibition assay

[0076] Table 3:

[0077] After 120 hours of drug treatment, 10 μL of CCK-8 detection reagent was added to each well of the cell plate using a multichannel pipette, and the cell plate was incubated for another 4 hours in a 37°C, 5% CO2 incubator. Finally, the absorbance of each well was measured at 450 nm using a microplate reader.

[0078] After the experiment, GraphPad Prism 8 software was used to analyze the inhibition percentage of the test drugs on the cells.

[0079] Calculation of inhibition percentage: Inhibition percentage = {[A(0 drug addition) - A(blank)] - [A(drug addition) - A(blank)]} / [A(0 drug addition) - A(blank)] × 100%

[0080] A (drug added): absorbance value of the wells with cells, CCK-8 solution and drug solution

[0081] A (blank): absorbance value of the well with culture medium and CCK-8 solution but no cells

[0082] A(0 drug addition): absorbance value of the well with cells and CCK-8 solution but no drug solution

[0083] The results of each group are shown in Figures 1 to 4. It can be seen that the killing effect of each combination on cells is better than that of the combination with AMG510.

[0084] Example 2: Study on the inhibitory activity of KRAS G12C inhibitor combined with two different FAK inhibitors on cell proliferation in vitro.

[0085] Except for some differences in the test compounds, the rest are the same as Example 1.

[0086] The grouping is shown in Table 3.

[0087] Table 3:

[0088] The information of some test compounds is shown in Table 4.

[0089] Table 4:

[0090] The results of each group are shown in Figures 5 to 7. It can be seen that the killing effect of each combination on cells is better than that of the combination with AMG510.

[0091] From the above description, those skilled in the art can easily determine the essential features of the present invention, and without departing from the spirit and scope of the present invention, various changes and modifications can be made to the present invention to adapt it to various uses and conditions. Therefore, other embodiments are also within the scope of the appended claims.

Claims

1. Use of a FAK inhibitor in the preparation of a medicament for treating tumors in combination with a KRAS G12C inhibitor, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

2. Use of a FAK inhibitor and a KRAS G12C inhibitor in the preparation of a medicament for treating tumors, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

3. A FAK inhibitor and a KRAS G12C inhibitor for treating tumors, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, a deuterated compound of Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

4. A method for treating tumors, comprising administering a FAK inhibitor and a KRAS G12C inhibitor to a subject, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

5. Use, FAK inhibitor, and KRAS G12C inhibitor or method according to any one of claims 1-4, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, deuterated compound 1 of Defactinib (CAS No 2384121-03-1), deuterated compound 2 of Defactinib (CAS No 2384120-99-2), or a pharmaceutically acceptable salt thereof. Further, the FAK inhibitor is Defactinib, AMP945, APG-2449 or Conteltinib.

6. Use, FAK inhibitor, and KRAS G12C inhibitor or method according to any one of claims 1-5, wherein the FAK inhibitor and the KRAS G12C inhibitor are administered simultaneously, separately or sequentially.

7. Use, FAK inhibitor, and KRAS G12C inhibitor or method according to any one of claims 1-6, wherein the FAK inhibitor is administered at a dose of about 25 mg / day - 1000 mg / day. Further, the FAK inhibitor is administered at a dose of about 25 mg / day - 500 mg / day.

8. Use, FAK inhibitor, and KRAS G12C inhibitor or method according to claim 7, wherein the KRAS G12C inhibitor is administered at a dose of about 100 mg / day - 2000 mg / day.

9. The use, FAK inhibitor and KRAS G12C inhibitor or method according to any one of claims 1-8, wherein, The tumor is a tumor with a KRAS mutation, and further is a tumor with a KRAS G12C mutation.

10. The use, FAK inhibitor and KRAS G12C inhibitor or method according to any one of claims 1-9, wherein, The tumor is adenocarcinoma of the lung, non-small cell lung cancer, colorectal cancer (CRC) (including colon cancer and rectal cancer), endometrial cancer, urothelial carcinoma of the bladder, invasive lobular carcinoma of the breast, squamous cell carcinoma of the cervix, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic cancer, biphasic pleural mesothelioma, clear cell renal cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, carcinosarcoma of the uterus, or malignant mixed Mullerian tumor of the uterus.

11. The use, FAK inhibitor and KRAS G12C inhibitor or method according to claim 10, wherein, The tumor is non-small cell lung cancer.

12. A pharmaceutical combination product, comprising: (a) an FAK inhibitor, and (b) a KRAS G12C inhibitor, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, a deuterated compound of Defactinib, a deuterated compound of AMP945, a deuterated compound of APG-2449, a deuterated compound of Conteltinib, or a pharmaceutically acceptable salt thereof, and the KRAS G12C inhibitor is RMC-4998, Divarasib, LY3537982, Opnurasib, or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical combination product according to claim 12, wherein the FAK inhibitor is Defactinib, AMP945, APG-2449, Conteltinib, deuterated compound 1 of Defactinib (CAS No 2384121-03-1), deuterated compound 2 of Defactinib (CAS No 2384120-99-2), or a pharmaceutically acceptable salt thereof. Further, the FAK inhibitor is Defactinib, AMP945, APG-2449 or Conteltinib.

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