Improved cancer treatment using a combination of SMARCA2 degraders and KRAS-targeted therapy

Abstract

Methods are described for treating SMARCA4-deficient cancer cells using selective SMARCA2 degraders and KRAS-targeted therapies in combination therapy.

Description

[Technical Field]

[0001] The present invention relates to the use of a combination of a SMARCA2 degrading agent and a KRAS targeted therapy to treat cancer. [Background technology]

[0002] Cell signaling is often dysregulated by genetic mutations in cancer cells, resulting in abnormal cell growth and proliferation. KRAS is one of the most important oncogenes for cancer cell signaling, activating RAF / MEK / ERK (MAPK) and PI3K signaling. The KRAS gene often expresses gain-of-function mutations. G12C (glycine 12 to cysteine) can be found in approximately 13% of lung cancers, 3% of colorectal cancers, and less frequently in uterine, pancreatic, breast, bladder, and ovarian cancers. Selective small molecule covalent inhibitors of KRAS G12C mutations have been developed by others and have shown promising clinical results (Huang L. et al., "KRAS Mutation: From Undruggable to Druggable in Cancer," Signal Transduct. Target Ther. (2021) 6:386; Skoulidis et al., "Sotorasib for Lung Cancers with KRAS p.G12C Mutation," N. Engl. J .Med. (2021) 384:2371-2381; Janne et al., "Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation," N. Engl. J .Med. (2022) 387:120-131). However, there remains a disappointing incidence of tumor recurrence after treatment with KRAS G12C inhibitors. Known mechanisms of relapse and resistance to KRAS G12C inhibitors include bypassing the KRAS G12C mutation (i.e., developing other mutations in the KRAS gene or other oncogenes) and reactivating cell signaling (Awad et al., "Acquired resistance to KRASG12C Inhibition in Cancer," N. Engl. J. Med. (2021) 384:2382-2393). Thus, there is a significant need to identify novel therapeutic strategies to delay and overcome such acquired resistance to KRAS G12C inhibitors.

[0003] SMARCA4 is a subunit of the mammalian SWItch / sucrose non-fermentable (mSWI / SNF) complex, which plays a key role in regulating gene expression by remodeling chromatin. Cancer cells expressing SMARCA4-deletion mutations depend on its paralogous gene, SMARCA2, for their survival.

[0004] The combination of a KRAS-targeted therapy with a SMARCA2-degrading agent has not previously been described. Summary of the Invention

[0005] The present disclosure provides a method for treating cancer, for example, SMARCA4 mutation, deletion or low expression cancer, by administering a therapeutically effective amount of combination therapy to a subject in need thereof, wherein the combination therapy comprises a therapeutically effective amount of SMARCA2 degrading agent or its pharmaceutically acceptable salt and a therapeutically effective amount of KRAS targeting therapy or its pharmaceutically acceptable salt.Compared with either SMARCA2 degrading agent or KRAS targeting therapy alone, the combination therapy described is safer and / or more effective in treating cancer. [Brief explanation of the drawings]

[0006] The foregoing summary, as well as the following detailed description, will be better understood when read in conjunction with the accompanying drawings, which show, by way of example, exemplary embodiments.

[0007] [Figure 1] FIG. 1 shows the incidence of SMARCA4 and KRAS mutations in the entire non-small cell lung cancer patient cohort (AACR Project GENIE Consortium) and that damaging mutations and genetic deletions of SMARCA4 frequently co-occur with KRAS G12C mutations in non-small cell lung cancer patients.

[0008] [Figure 2]1 shows that the combination of compound 1 and KRAS G12C inhibitors exhibits synergistic anti-proliferative effects in lung cancer cells (NCI-H2030). Lung cancer NCI-H2030 cells (SMARAC4 low / KRAS G12C) were treated with KRAS G12C inhibitors (MRTX849, AMG510, ARS1629, or JDQ-443) and with different dose ranges of SMARCA2 degraders (compound 1), and cell viability was analyzed on day 7 using Cell-titer Glo.

[0009] [Figure 3] Combination of Compound 1 with KRAS G12C inhibitors shows synergistic anti-proliferative effects in bladder cancer cells (UM-UC-3). Bladder cancer UM-UC-3 cells (SMARAC4 damaging mutation / KRAS G12C) were treated with KRAS G12C inhibitors (MRTX849, AMG510, ARS1629, or JDQ443) and with different dose ranges of a SMARCA2 degrader (Compound 1), and cell viability was analyzed on day 7 using Cell-titer Glo.

[0010] [Figure 4] Cell lines without SMARCA4 deletion or KRAS mutation showed no synergistic effect. Figure 1 shows lung cancer NCI-H838 cells (SMARAC4 damaging mutation / KRAS WT) or NCI-H358 cells (SMARCA4 WT / KRAS G12C) were treated with KRAS G12C inhibitors (MRTX849 or AMG510) and with different dose ranges of a SMARCA2 degrader (compound 1), and cell viability was analyzed on day 7 using Cell-titer Glo.

[0011] [Figure 5] FIG. 1 shows Bliss and ZIP synergy scores for H2030 cells treated with a SMARCA2 degrader (compound 1) and a KRAS-targeted therapy (MRTX849, AMG510, ARS1629 or JDQ443), and that synergy is likely when the synergy score is greater than 10.

[0012] [Figure 6] FIG. 1 shows Bliss and ZIP synergy scores for UM-UC-3 cells treated with a SMARCA2 degrader (compound 1) and a KRAS-targeted therapy (MRTX849, AMG510, ARS1629 or JDQ443), and that synergy is likely when the synergy score is greater than 10.

[0013] [Figure 7] FIG. 1 shows a plot of mean tumor volume versus time of administration for UM-UC-3 cells treated with a SMARCA2 degrader (Compound 1) and a KRAS targeted therapy (MRTX849).

[0014] [Figure 8] FIG. 1 shows a plot of mean tumor volume versus time of administration for H2030 cells treated with a SMARCA2 degrader (Compound 1) and a KRAS targeted therapy (MRTX849).

[0015] DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The present disclosure may be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods that are described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are described for brevity in the context of a single aspect may also be provided separately or in any subcombination. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the disclosure.

[0016] In this disclosure, the singular forms "a," "an," and "the" include plural references, and reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise. Thus, for example, a reference to a "compound" is a reference to one or more of such compounds known to those of skill in the art and equivalents thereof, and so forth. The term "plurality," as used herein, means two or more.

[0017] Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limit of that range, to one-tenth of the unit of the lower limit, and any other stated or intervening value in that stated range, is encompassed within the disclosure, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the upper or lower limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0018] When a range of values ​​is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

[0019] The term "administration" refers to the direct administration of a compound of the invention, or a composition containing the compound, to a subject. In other aspects, "administration" refers to the administration of a prodrug, derivative, or analog, or compound of the invention, which results in the formation of an equivalent amount of the compound in the body.

[0020] As used herein, the term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers, diastereomers, tautomers.

[0021] The terms "patient" and "subject" are used interchangeably throughout this specification to describe an animal, e.g., a mammal, to which treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided. Mammals that can be treated using the methods of the present disclosure include rodents, such as mice, rats, rabbits, guinea pigs, and the like, as well as domestic animals, such as dogs, cats, and livestock, such as horses, cows, and sheep. In other aspects, the mammal is a human.

[0022] As used above and throughout this disclosure, the term "therapeutically effective amount" refers to an amount effective at the dosage and duration necessary to achieve the desired results in treating the relevant disorder, condition, or side effect. Of course, the effective amount of the components of the present invention will vary from subject to subject, depending not only on the specific compound, selected component or composition, route of administration, and the component's ability to elicit the desired results in the individual, but also on the condition or severity of the disease to be alleviated, hormone levels, age, sex, individual weight, the subject's condition, the severity of the condition being treated, any concomitant medications or special diets followed by a particular patient, and other factors that a person skilled in the art would recognize. A therapeutically effective amount is also an amount in which any toxic or harmful effects of the component are outweighed by the therapeutically beneficial effects.

[0023] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of the federal or state government or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, e.g., humans.

[0024] "Pharmaceutically acceptable salts" refers to salts of compounds of the present disclosure that are pharmaceutically acceptable and that possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specific examples of such salts include the following: (1) salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, and glucoheptonic acid; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0025] A "pharmaceutically acceptable excipient" refers to a non-toxic, biologically acceptable, and otherwise biologically suitable substance for administration to a subject, such as an inert substance that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a drug and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. See, for example, Remington, JP (2020), Remington, the science and practice of Pharmacy, Elsevier Science.

[0026] "Treating" or "treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (i.e., preventing or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0027] The present disclosure is directed to a method for treating cancer in a subject in need thereof.According to these methods, a combination therapy comprising a SMARCA2 degrading agent or its pharmaceutically acceptable salt and a KRAS targeting therapy or its pharmaceutically acceptable salt is administered to the subject.The SMARCA2 degrading agent (or its salt) and the KRAS targeting therapy (or its salt) are each administered in an amount that is therapeutically effective in treating cancer.

[0028] The combination therapy described herein is surprising because it at least exhibits synergistic effects and provides safer and / or more effective cancer therapy.As used herein, "safer" means that the therapy exhibits less severe or fewer adverse events or can be administered at a lower dose compared to a therapy that is not within the scope of the present disclosure.As used herein, "more effective" means that the therapy produces a more rapidly observed or more significant therapeutic effect compared to a therapy that is not within the scope of the present disclosure.

[0029] As described herein, administration of a combination therapy comprising a SMARCA2 degrading agent and a KRAS targeted therapy in treating a subject's cancer is safer and / or more effective than a method of treating a subject's cancer by administering a SMARCA2 degrading agent without a KRAS targeted therapy. Additionally, or alternatively, administration of a combination therapy comprising a SMARCA2 degrading agent and a KRAS targeted therapy in treating a subject's cancer is safer and / or more effective in treating a subject's cancer than a method of treating a subject's cancer by administering a KRAS targeted therapy without a SMARCA2 degrading agent.

[0030] In other embodiments, administration of a combination therapy comprising a SMARCA2 degrading agent and a KRAS targeted therapy in treating a subject's cancer is safer and / or more effective than a method of treating a subject's cancer that includes administering a SMARCA2 degrading agent but not a KRAS targeted therapy. Additionally, or alternatively, administration of a combination therapy comprising a SMARCA2 degrading agent and a KRAS targeted therapy in treating a subject's cancer is safer and / or more effective than a method of treating a subject's cancer that includes administering a KRAS targeted therapy but not a SMARCA2 degrading agent.

[0031] The synergistic effects of the combination therapies disclosed herein provide safer and / or more effective cancer treatments than existing cancer treatments.

[0032] For example, the synergistic effect of administering the described combination therapy can be achieved when the compounds of the present disclosure are administered together in a single unit dosage form.Alternatively, the synergistic effect of administering the described combination therapy can be achieved when the SMARCA2 degrading agent and KRAS targeting therapy are each administered as their own separate unit dosage form.According to these embodiments, the SMARCA2 degrading agent and KRAS targeting therapy can be administered to the subject at approximately the same time.In other of these embodiments, the SMARCA2 degrading agent and KRAS targeting therapy can be administered at different times, for example, at different times of the day or on different days.

[0033] According to the present disclosure, the SMARCA2 degrading agent can be any SMARCA2 degrading agent known in the art. According to the present disclosure, "SMARCA2 degrading agent" includes small molecules, for example, molecules having a molecular weight of 1000 g / mol or less in free base form. According to the present disclosure, these SMARCA2 degrading agents induce SMARCA2 degradation, resulting in a reduction in SMARCA2 protein levels in cells and suppression of the growth of SMARCA4-deficient cancer cells. Preferably, the SMARCA2 degrading agent is a small molecule that induces a greater than 50% reduction in SMARCA2 protein in cells, as detected by Western blot, ELISA, HiBiT degradation assay, or any other method used in the art for detecting protein levels. Exemplary SMARCA2 degrading agents are described in International Publication No. 2022099117 and are molecules that induce a greater than 50% reduction in SMARCA2 protein in cells, as detected by HiBiT degradation assay. The SMARCA2 degrading agents used in the described methods can be administered via any suitable route of administration, including orally, subcutaneously, or intravenously.

[0034] SMARCA2 degraders useful in the methods of the present disclosure include, for example, those described in PCT Application WO 2022099117, as well as U.S. Provisional Patent Application No. 63 / 280,205, U.S. Provisional Patent Application No. 63 / 280,206, U.S. Provisional Patent Application No. US63 / 318,984, U.S. Provisional Patent Application No. 63 / 320,573, U.S. Provisional Patent Application No. 63 / 320,597, U.S. Provisional Patent Application No. 63 / 340,185, and U.S. Provisional Patent Application No. 63 / 344,901, the disclosures of each of which are incorporated herein by reference.

[0035] In certain embodiments, the SMARCA2 degrader is Compound 1. [ka]

[0036] Stereoisomers of Compound 1 are also useful in the methods of the present disclosure.

[0037] According to the present disclosure, the KRAS targeted therapy can be any KRAS targeted therapy known in the art. According to the present disclosure, the KRAS targeted therapy can include an mRNA vaccine targeting KRAS mutant cancer. Also according to the present disclosure, the KRAS targeted therapy is a KRAS-targeted small molecule, such as a small molecule inhibitor or a bispecific degrader (see, for example, the targeted protein degraders described in Miklos Bekes, PROTAC targeted protein degraders: the past is prologue, Nature Reviews Drug Discovery, volume 21, pp. 181-200 (2022)). A small molecule KRAS targeted therapy is a molecule having a molecular weight of less than 1000 g / mol in its free base form.

[0038] According to the present disclosure, the KRAS targeted therapy useful in the described methods is a "KRAS inhibitor." As used herein, a KRAS inhibitor refers to: [ka] Compounds that inhibit the biological activity of mutant proteins while sparing wild-type KRAS proteins, which [ka] This is supported by observations that selectively inhibit the growth of cancer cell lines expressing KRAS G12C inhibitors. See Albert Kwan, "The path to the clinic: a comprehensive review on direct KRAS G12C inhibitors," Journal of Experimental & Clinical Cancer Research, volume 41, 2022. According to the present disclosure, the mRNA vaccine is an mRNA-derived KRAS-targeted vaccine, such as the mRNA 5671 vaccine described at www.cancer.gov / publications / dictionaries / cancer-drug / def / mrna-derived-kras-targeted-vaccine-v941. Also present within the present disclosure is a lipid nanoparticle (LNP)-formulated mRNA-based cancer vaccine targeting four of the most commonly occurring KRAS mutations (G12D, G12V, G13D, and G12C) with potential immunostimulatory and antitumor activities.

[0039] The KRAS targeted therapies used in the described methods can be administered via any suitable route of administration, including orally, subcutaneously, or intravenously.

[0040] In some embodiments of the present disclosure, KRAS target therapy is KRAS G12 inhibitor, for example, KRAS G12C inhibitor, KRAS G12D inhibitor, KRAS G12V inhibitor, or a combination thereof.In some embodiments, KRAS target therapy is KRAS Q61 inhibitor, for example, KRAS Q61K inhibitor, KRAS Q61H inhibitor, or a combination thereof.In some embodiments, KRAS target therapy is a bispecific KRAS target degrader.In some embodiments, KRAS target therapy is an mRNA vaccine that targets KRAS mutation cancer.

[0041] In certain embodiments, the KRAS targeted therapy is adagrasib (MRTX849), sotorasib (AMG510), JDQ443, or a combination thereof. [ka]

[0042] In some embodiments of the disclosure, the SMARCA2 degrader used in combination is Compound 1 and the KRAS targeted therapy is adagrasib (MRTX849).

[0043] In some embodiments of the present disclosure, the SMARCA2 degrader used in combination is Compound 1 and the KRAS targeted therapy is sotorasib.

[0044] In some embodiments of the disclosure, the SMARCA2 degrader used in combination is Compound 1 and the KRAS targeted therapy is JDQ444.

[0045] The disclosed combination therapies are useful for treating or preventing diseases or disorders mediated by SWI / SNF mutations.

[0046] The disclosed combination therapies are used to treat cancer, such as SMARCA4-deficient cancers, which can be identified using methods known to those skilled in the art.

[0047] In some embodiments, the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphoma, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, neuroblastoma, and leukemia. Sarcomas, including glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. Additional cancers that may be treated using compounds according to the present disclosure include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, B-cell precursor ALL, B-cell precursor lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0048] In some embodiments, the cancer is lung cancer, e.g., small cell lung cancer or non-small cell lung cancer. In some embodiments, the lung cancer is squamous non-small cell lung cancer or non-squamous non-small cell lung cancer, e.g., adenocarcinoma or large cell carcinoma.

[0049] In some embodiments, the cancer is breast cancer, pancreatic cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, squamous cell lung carcinoma, squamous cell carcinoma of the head and neck, esophageal cancer, gastric cancer, colon adenocarcinoma, bladder cancer, uterine adenocarcinoma, endometrioid adenocarcinoma, skin cancer, melanoma, or lung adenocarcinoma.

[0050] In some embodiments, the cancer is uterine adenocarcinoma.

[0051] In certain embodiments, the target protein is SMARCA2, SMARCA4, and / or PB1.

[0052] In certain embodiments, the target protein complex is SWI / SNF in a cell.

[0053] In certain further embodiments, the cancer is a SMARCA2- and / or SMARAC4-dependent cancer.

[0054] In certain embodiments, the present invention provides pharmaceutical compositions for use when the SMARCA2- and / or SMARCA4-dependent disease or disorder is cancer.

[0055] Pharmaceutical compositions useful in the described methods The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the compounds of the present disclosure, or their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives as an active ingredient. If desired, the pharmaceutical compositions contain pharmaceutically acceptable salts and / or coordination complexes thereof, as well as one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0056] This pharmaceutical composition can be administered alone or in combination with one or more other drugs, which are also typically administered in the form of a pharmaceutical composition.If desired, one or more compounds of the present invention and other drugs can be mixed in a preparation, or both components can be formulated in separate preparations and used separately or in combination at the same time.

[0057] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11% 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.00 Less than 5%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number within a range defined by and including any two of the above numbers) w / w, w / v, or v / v.

[0058] In some embodiments, the concentration of one or more compounds of the present invention is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.0 Greater than 5%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number within a range defined by and including any two of the above numbers) w / w, w / v, or v / v.

[0059] In some embodiments, the concentration of one or more compounds of the present invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 10%, from about 0.09% to about 12%, from about 0.10% to about 13%, from about 0.11% to about 14%, from about 0.12% to about 15%, from about 0.13% to about 16%, from about 0.14% to about 17%, from about 0.15% to about 18%, from about 0.16% to about 19%, from about 0.17% to about 20%, from about 0.18% to about 22%, from about 0.19% to about 23%, from about 0.19% to about 24%, from about 0.19% to about 25%, from about 0.19% to about 26%, from about 0.19% to about 27%, from about 0.19% to about 28%, from about 0.19% to about 29%, from about 0.19% to about 26%, from about 0.19% to about 25%, from about 0.19% to about 26%, from about 0.19% to about 28%, from about 0.19% to about 29%, from about 0.19% to about 29%, from about 0.19% to about 25%, from about 0.19% to about 26%, from about % to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v, or v / v.

[0060] In some embodiments, the concentration of one or more compounds of the present invention is within the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% w / w, w / v, or v / v.

[0061] In some embodiments, the amount of one or more compounds of the present invention is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.04 g, 0.05 ... g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in a range defined by and including any two of the above numbers).

[0062] In some embodiments, the amount of one or more compounds of the present invention is 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number within a range defined by and including any two numbers above).

[0063] In some embodiments, the amount of one or more compounds of the present invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0064] Pharmaceutical compositions of the present invention typically comprise an active ingredient of the present invention (e.g., a compound of the present disclosure) or a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0065] Pharmaceutical composition for oral administration In some embodiments, the present invention provides pharmaceutical compositions for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0066] In some embodiments, a pharmaceutical composition for oral administration comprises a KRAS targeted therapy and a pharmaceutical excipient suitable for oral administration.

[0067] In some embodiments, the pharmaceutical composition for oral administration comprises a SMARCA2 degrading agent and a pharmaceutical excipient suitable for oral administration.

[0068] In some embodiments, a pharmaceutical composition for oral administration comprises a KRAS targeted therapy and a SMARCA2 degrading agent, and a pharmaceutical excipient suitable for oral administration.

[0069] In some embodiments, a dose of a KRAS targeted therapy is administered to the subject, and a dose of a SMARCA2 degrading agent is administered to the subject. In some embodiments, the KRAS targeted therapy and the SMARCA2 degrading agent are administered simultaneously.

[0070] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration containing (i) an effective amount of a compound of the present invention, optionally (ii) an effective amount of a second pharmaceutical agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains (iv) an effective amount of a third pharmaceutical agent.

[0071] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion. Pharmaceutical compositions of the present invention suitable for oral administration can be provided in discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any method of pharmacy, but all methods include the step of bringing the active ingredient into association with a carrier that constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with excipients, such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersants, in a suitable machine. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0072] Because water can accelerate the degradation of some compounds, the present invention further encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients. For example, water can be added (e.g., 5%) in pharmaceutical applications as a means of simulating long-term storage to determine characteristics such as shelf life or the stability of a formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water, allowing them to be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers, blister packs, and strip packs.

[0073] The active ingredient can be mixed in an intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.Carriers can take a variety of forms, depending on the preparation form desired for administration.In preparing compositions for oral dosage forms, any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used as carriers for oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used for oral solid preparations, in some embodiments, without using lactose.For example, suitable carriers include powders, capsules, and tablets with solid oral preparations.If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0074] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as gum acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0075] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0076] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Using too much disintegrant can result in tablets that disintegrate in the bottle. Using too little can result in insufficient disintegration, which can alter the rate and extent of release of the active ingredient from the dosage form. Therefore, a dosage form of the compound disclosed herein can be formed using a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient. The amount of disintegrant used can vary based on the type of formulation and mode of administration and can be readily discerned by those skilled in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0077] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants can optionally be added in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0078] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, along with various sweetening or flavoring agents, coloring agents or dyes, and, if desired, emulsifying and / or suspending agents.

[0079] Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used.The preparation for oral use can also be provided as a hard gelatin capsule, in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule, in which the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0080] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0081] Suitable hydrophilic surfactants will generally have an HLB value of at least 10, while suitable lipophilic surfactants will generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have higher solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have higher solubility in aqueous solutions.

[0082] Hydrophilic surfactants are generally considered to be compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (e.g., hydrophobic) surfactants are compounds having an HLB value of about 10 or less. However, the HLB value of a surfactant is only a rough guideline that is commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0083] Hydrophilic surfactants can be either ionic or nonionic.Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidate salts, fatty acid derivatives of amino acids, oligopeptides, and polypeptides, glyceride derivatives of amino acids, oligopeptides, and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and their derivatives, lysophospholipids and their derivatives, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0084] Among the aforementioned groups, ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0085] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactate, stearoyl lactate, succinyl The ionic forms may be acetylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0086] Hydrophilic nonionic surfactants include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols, polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters, polyethylene glycol glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters, hydrophilic interesterification products of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols, polyoxyethylene sterols, derivatives and analogs thereof, polyoxyethylated vitamins and derivatives thereof, polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof, polyethylene glycol sorbitan fatty acid esters, and hydrophilic interesterification products of polyols and at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0087] Other hydrophilic nonionic surfactants include PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PE G-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG -40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprate / Caprylate Glyceride, PEG-8 Caprate / Caprylate Glyceride, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soysterol, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether , POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol, PEG15-100 octylphenol, and poloxamer.

[0088] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, mono- and diglyceride lactic acid derivatives, the hydrophobic transesterification product of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, fat-soluble vitamins / vitamin derivatives, and mixtures thereof.In this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or the hydrophobic transesterification product of polyols and at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0089] In one embodiment, the composition may contain a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and minimize precipitation of the compound of the present invention. This may be particularly important for compositions for parenteral use, such as injection compositions. Solubilizing agents may also be added to increase the solubility of hydrophilic drugs and / or other components (e.g., surfactants) or to maintain the composition as a stable or homogeneous solution or dispersion.

[0090] Examples of suitable solubilizers include alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives, ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG, amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-acetylglucosamine, methyl ... Examples of suitable solubilizing agents include, but are not limited to, alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0091] A mixture of solubilizers may be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0092] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer can be limited to a biologically acceptable amount, which can be easily determined by one skilled in the art. In some situations, for example, to maximize the drug concentration, it may be advantageous to include an amount of solubilizer that far exceeds the bioacceptable amount, with the excess solubilizer being removed using conventional techniques such as distillation or evaporation before providing the composition to a subject. Thus, when present, the solubilizer can be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, can also be used. Typically, the solubilizer may be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0093] The composition can further comprise one or more pharmaceutically acceptable additives and excipients, including, but not limited to, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, coloring agents, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0094] In addition, acids or bases may be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable are bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, can also be used. When the base is a salt, the cation can be any convenient pharmaceutically acceptable cation, such as ammonium, an alkali metal, or an alkaline earth metal. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0095] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0096] Injectable pharmaceutical composition In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a compound of the present invention and a pharmaceutical excipient suitable for injection, wherein the components and amounts of the drugs in the composition are as described herein.

[0097] Forms into which the novel compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions or emulsions including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0098] Aqueous solutions in physiological saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0099] Sterile injectable solution is prepared by incorporating the compound of the present invention in the required amount into a suitable solvent with various other components as listed above as necessary, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other necessary components from those listed above.For the preparation of sterile powder for sterile injectable solution, the preferred method of preparation is vacuum drying and freeze-drying technology, these techniques produce powder of active ingredient with any other desired components from the solution that has been previously sterilized and filtered.

[0100] The administration of the compound or pharmaceutical composition of the present invention can be carried out by any method that allows the compound to be delivered to the site of action.These methods include oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), local (for example, transdermal application), rectal administration, administration via local delivery by catheter or stent, or administration via inhalation.The compound can also be administered intraadiposely or intrathecally.

[0101] In some embodiments, the compounds or pharmaceutical compositions of the present invention are administered by intravenous injection.

[0102] The pharmaceutical composition may be, for example, in the form of a sustained-release formulation, solution, or suspension; as a sterile solution, suspension, or emulsion for parenteral injection; as an ointment or cream for topical administration; or as a suppository for rectal administration. The pharmaceutical composition may be in a unit dosage form suitable for single administration of a precise dose. The pharmaceutical composition comprises a conventional pharmaceutical carrier or excipient and a compound according to the present invention as an active ingredient. In addition, it may contain other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0103] Exemplary parenteral dosage forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0104] The compounds of the present disclosure and pharmaceutical compositions comprising them can be administered alone or in combination with medical therapy to treat any of the diseases described.Medical therapy includes, for example, surgery and radiotherapy (e.g., gamma irradiation, neutron beam radiotherapy, electron beam radiotherapy, proton beam therapy, brachytherapy, whole-body radioisotope).

[0105] In other embodiments, the combination therapies described can be administered alone or in combination with one or more other agents.

[0106] For the treatment of cancer and other proliferative diseases, the described therapeutic methods may further include combination with other chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. The described methods may also be used in combination with medical therapies such as surgery or radiation therapy, e.g., gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes.

[0107] Nothing in this specification should be deemed to limit the scope of the present disclosure. All examples presented are representative and non-limiting. The above-described embodiments may be modified or varied as understood by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the claims and their equivalents, the embodiments disclosed herein may be practiced otherwise than as specifically described. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entirety.

[0108] The present disclosure is also directed to the following aspects: 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a combination therapy, the combination therapy comprising: a therapeutically effective amount of a SMARCA2 degrader, or a pharmaceutically acceptable salt thereof, and comprising a therapeutically effective amount of a KRAS targeted therapy, or a pharmaceutically acceptable salt thereof; The administration of the combination therapy in treating cancer in a subject can provide cancer treatment in a subject in need thereof. administering a SMARCA2 degrading agent without a KRAS-targeted therapy; administering a KRAS-targeted therapy without a SMARCA2-degrading agent; or A method that is safer and / or more effective than a combination thereof.

[0109] 2. The method of aspect 1, wherein the SMARCA2 degrader is Compound 1, or a pharmaceutically acceptable salt thereof. [ka]

[0110] 3. The method of any one of aspects 1-2, wherein the KRAS targeted therapy is a KRAS inhibitor.

[0111] 4. The method of embodiment 3, wherein the KRAS inhibitor is a KRAS G12 inhibitor.

[0112] 5. The method of embodiment 4, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor, a KRAS G12D inhibitor, or a KRAS G12V inhibitor.

[0113] 6. The method of embodiment 5, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor.

[0114] 7. The method of embodiment 5, wherein the KRAS G12 inhibitor is a KRAS G12D inhibitor.

[0115] 8. The method of embodiment 5, wherein the KRAS G12 inhibitor is a KRAS G12V inhibitor.

[0116] 9. The method of embodiment 3, wherein the KRAS inhibitor is a KRAS Q61 inhibitor.

[0117] 10. The method of embodiment 9, wherein the KRAS Q61 inhibitor is a KRAS Q61K or KRAS Q61H inhibitor.

[0118] 11. The method of embodiment 10, wherein the KRAS Q61 inhibitor is a KRAS Q61K inhibitor.

[0119] 12. The method of embodiment 10, wherein the KRAS Q61 inhibitor is a KRAS Q61H inhibitor.

[0120] 13. The method of any one of aspects 1-2, wherein the KRAS targeted therapy is a bispecific KRAS targeted degrader.

[0121] 14. The method of any one of aspects 1 to 2, wherein the KRAS targeted therapy is an mRNA vaccine that targets KRAS mutant cancer.

[0122] 15. KRAS targeted therapy is [ka] or a pharmaceutically acceptable salt thereof.

[0123] 16. KRAS targeted therapy is [ka] or a pharmaceutically acceptable salt thereof.

[0124] 17. KRAS targeted therapy is [ka] or a pharmaceutically acceptable salt thereof.

[0125] 18. The method of any one of aspects 1 to 17, wherein the cancer is a SMARCA4-deficient cancer.

[0126] 19. Cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, 19. The method of any one of aspects 1-18, wherein the cancer is a sarcoma, including ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. Additional cancers that may be treated using compounds according to the present disclosure include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, B-cell precursor ALL, B-cell precursor lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0127] 20. The method of aspect 19, wherein the lung cancer is small cell lung cancer or non-small cell lung cancer.

[0128] 21. The method of aspect 19 or 20, wherein the lung cancer is squamous non-small cell lung cancer, or non-squamous non-small cell lung cancer, such as adenocarcinoma or large cell carcinoma.

[0129] 22. The method of any one of aspects 1-19, wherein the cancer is breast cancer, pancreatic cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, head and neck squamous cell carcinoma, esophageal cancer, gastric cancer, colon adenocarcinoma, bladder cancer, uterine adenocarcinoma, endometrioid adenocarcinoma, skin cancer, melanoma, or lung adenocarcinoma.

[0130] 23. The method of any one of aspects 1 to 19, wherein the cancer is non-small cell lung cancer.

[0131] 24. The method of any one of aspects 1 to 19, wherein the cancer is uterine adenocarcinoma.

[0132] 25. The method of any one of aspects 1 to 19, wherein the cancer is endometrioid adenocarcinoma.

[0133] 26. The method of any one of aspects 1-19, wherein the cancer is colon adenocarcinoma.

[0134] 27. The method of any one of aspects 1 to 19, wherein the cancer is ovarian cancer.

[0135] 28. The method of any one of aspects 1 to 27, wherein the amount of the SMARCA2 degrading agent administered is from about 1 mg / kg to about 50 mg / kg.

[0136] 29. The method of any one of aspects 1-28, wherein the amount of KRAS targeted therapy administered is from about 1 mg / kg to about 50 mg / kg of the subject.

[0137] 30. SMARCA2 degraders are [ka] or a pharmaceutically acceptable salt thereof; KRAS targeted therapy [ka] 30. The method of any one of aspects 1 to 29, wherein the compound is a pharmaceutically acceptable salt thereof.

[0138] 31. SMARCA2 degraders are [ka] or a pharmaceutically acceptable salt thereof; KRAS targeted therapy [ka] 30. The method of any one of aspects 1 to 29, wherein the compound is a pharmaceutically acceptable salt thereof.

[0139] 32. A pharmaceutical combination comprising: a SMARCA2 degrading agent or a pharmaceutically acceptable salt thereof; a KRAS targeted therapy or a pharmaceutically acceptable salt thereof; as a pharmaceutically acceptable excipient.

[0140] 33. SMARCA2 degraders are [ka] or a pharmaceutically acceptable salt thereof.

[0141] 34. KRAS targeted therapy is [ka] 34. A combination according to any of aspects 32-33, wherein the combination is:

[0142] 35. KRAS targeted therapy is [ka] 35. A combination according to any of aspects 33-34, wherein the combination is:

[0143] 36. KRAS targeted therapy is [ka] 35. A combination according to any of aspects 33-34, wherein the combination is:

[0144] 7. A combination according to any one of aspects 33 to 36, wherein the KRAS targeted therapy is a KRAS inhibitor.

[0145] 38. The combination according to aspect 37, wherein the KRAS inhibitor is a KRAS G12 inhibitor.

[0146] 39. The combination according to aspect 38, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor, a KRAS G12D inhibitor, or a KRAS G12V inhibitor.

[0147] 40. The combination according to aspect 39, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor.

[0148] 41. A combination according to aspect 39, wherein the KRAS G12 inhibitor is a KRAS G12D inhibitor.

[0149] 42. A combination according to embodiment 39, wherein the KRAS G12 inhibitor is a KRAS G12V inhibitor.

[0150] 43. A combination according to any one of aspects 33 to 36, wherein the KRAS targeted therapy is a KRAS Q61 inhibitor.

[0151] 44. A combination according to aspect 43, wherein the KRAS Q61 inhibitor is a KRAS Q61K or KRAS Q61H inhibitor.

[0152] 45. A combination according to aspect 44, wherein the KRAS Q61 inhibitor is a KRAS Q61K inhibitor.

[0153] 46. ​​A combination according to aspect 44, wherein the KRAS Q61 inhibitor is a KRAS Q61H inhibitor.

[0154] 47. A combination according to any one of aspects 33 to 36, wherein the KRAS targeted therapy is a bispecific KRAS targeted degrader.

[0155] 48. The combination of any one of aspects 33 to 36, wherein the KRAS targeted therapy is an mRNA vaccine targeting KRAS mutant cancer. [Example]

[0156] The degree of combination synergy or antagonism is quantified by comparing the observed drug combination response to the expected response calculated using a reference model that assumes no drug-drug interactions. Drug synergy was determined using the Bliss and Zero Interaction Potency (ZIP) reference models. These models quantify the degree of synergy as the multiplicative effect of single drugs as if they acted alone (Bliss), or the expected response corresponding to the effect as if the single drugs did not affect each other's efficacy (ZIP).

[0157] The Bliss independence model assumes a stochastic process in which two drugs exert their effects independently, allowing the expected combination effect to be calculated based on the probability of independent events. The ZIP model captures drug interaction relationships by comparing the change in potency (effect at a specific dose level) of the dose-response curve between individual drugs and their combination. ZIP assumes that two non-interacting drugs are expected to produce minimal changes in their dose-response curves. The model calculations can be found at www.ncbi.nlm.nih.gov / pmc / articles / PMC4759128 / .

[0158] Cell proliferation assay: Cells were seeded in 384-well white-walled, clear-bottom plates under standard tissue culture conditions. NCI-H2030 (ATCC, CRL-5914) cell line was seeded at 250 cells per well in RPMI-1640 medium with FBS serum to a final concentration of 10%. UM-UC-3 (ATCC, CRL-1749) cell line was seeded at 100 cells per well in EMEM medium with FBS serum to a final concentration of 10%. The day after seeding, serial dilutions of two compounds were seeded in quadruplicate as a dose-response matrix, including a DMSO control, using a Tecan D300e Digital Dispenser (Tecan Group Ltd., Mannedorf, Switzerland). All wells were normalized to the maximum total volume of DMSO. After 7 days, the cell viability effects of drug combinations were measured using the CellTiter-Glo® 2.0 Cell Viability Assay (CTG) (#G9242, Promega, Madison, WI). SynergyFinder (Ianevski et al., 2020) was used to calculate predicted drug combination responses based on the Bliss and ZIP reference models. Positive and negative deviations between the observed and predicted responses indicate synergy and antagonism, respectively. Bliss and ZIP scores are summarized in Figures 5 and 6. Synergy is likely when a synergy score is greater than 10. MRTX849 (adagrasib, catalog number S8884) and ARS-1620 (catalog number S8707) were purchased from Selleck Chemicals. AMG510 (sotorasib, catalog number HY-114277) and JDQ-443 (catalog number HY-139612) were purchased from MedChemExpress.

[0159] Example 1 Excellent synergy was observed between compound 1 and KRAS G12C inhibitors (MRTX849, AMG510, ARS-1620, or JDQ-443) in lung cancer cell lines (NCI-H2030). NCI-H2030 is a non-small cell lung cancer cell line that expresses low SMARCA4 and KRAS G12C mutations. Combination therapy was applied to H2030 cells, and the % viable cells were calculated (see Figure 2). The Bliss score and ZIP score were greater than 10, indicating that compound 1 and KRAS G12C inhibitors likely exhibit synergistic effects (Figure 5).

[0160] Example 2 Excellent synergy was also observed in a bladder cancer cell line (UM-UC-3). UC-UM-3 is a human bladder transitional cell carcinoma cell line expressing a damaging SMARCA4 mutation and a KRAS G12C mutation. Combination therapy was applied to UM-UC-3 cells, and the % viable cells were calculated (Figure 3). The Bliss and ZIP scores were greater than 10, indicating that compound 1 and the KRAS G12C inhibitor likely exhibit synergistic effects (Figure 6).

[0161] These results demonstrate that combination therapy of the SMARCA2 protein degrader Compound 1 and KRAS-targeted therapy exhibits a potent synergistic interaction in SMARCA4-deficient and KRAS G12C mutation-expressing cell lines in vitro.

[0162] Example 3 A significant synergistic effect was also observed in the bladder cancer cell line (UM-UC-3) with respect to tumor volume reduction. Combination therapy applied to UM-UC-3 cells demonstrated synergistic effects on tumor volume reduction, as shown in Figure 7. Compound 1 was administered subcutaneously at a concentration of 100 mg / kg Q3D (once every three days). MRTX849 was administered orally at a concentration of 10 mg / kg QD (once daily). Statistical analysis used a two-tailed Mann-Whitney test versus vehicle, with *P<0.05, **P<0.01, and ***P<0.001.

[0163] These results suggest that the combination of the SMARCA2 protein degrader Compound 1 with KRAS-targeted therapy can slow tumor growth. The combined therapy, administered to mice bearing UM-UC-3 xenograft tumors, demonstrated a synergistic effect on tumor volume reduction.

[0164] Furthermore, Figure 4 shows two control lines, H838 and H358. H838 does not have a KRAS G12C mutation, and H358 does not have a SMARCA4 mutation. No synergy was observed. Therefore, synergy was observed only in cancer cells with both SMARCA4 and KRAS G12C mutations.

[0165] Example 4 A significant synergistic effect was also observed in the lung cancer cell line (NCI-H2030) with respect to tumor volume reduction. Combination therapy applied to H2030 cells demonstrated synergistic effects on tumor volume reduction, as shown in Figure 8. Compound 1 was administered subcutaneously at a concentration of 100 mg / kg Q3D. MRTX849 was administered orally at a concentration of 10 mg / kg QD. Statistical analysis used a two-tailed Mann-Whitney test versus vehicle, with *P<0.05, **P<0.01, and ***P<0.001.

[0166] These results indicate that the combination of the SMARCA2 protein degrader Compound 1 with KRAS-targeted therapy can slow tumor growth. The combined therapy, administered to mice bearing H2030 xenograft tumors, demonstrated a synergistic effect on tumor volume reduction.

Claims

1. 1. A method of treating cancer in a subject in need thereof, comprising administering a combination therapy to the subject, the combination therapy comprising: a therapeutically effective amount of a SMARCA2 degrading agent or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of a KRAS targeted therapy or a pharmaceutically acceptable salt thereof; The administration of the combination therapy in treating cancer in the subject may provide treatment for cancer in a subject in need thereof: administering the SMARCA2 degrading agent without the KRAS targeted therapy; or A method that is safer and / or more effective compared to administering the KRAS targeted therapy without the SMARCA2 degrading agent.

2. The method of claim 1, wherein the SMARCA2 degrading agent is Compound 1, or a pharmaceutically acceptable salt thereof. 【Chemical 1】

3. 3. The method of claim 1 or 2, wherein the KRAS targeted therapy is a KRAS inhibitor.

4. The method of claim 3, wherein the KRAS inhibitor is a KRAS G12 inhibitor.

5. The method of claim 4, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor, a KRAS G12D inhibitor, or a KRAS G12V inhibitor.

6. The method of claim 5, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor.

7. The method of claim 5, wherein the KRAS G12 inhibitor is a KRAS G12D inhibitor.

8. The method of claim 5, wherein the KRAS G12 inhibitor is a KRAS G12V inhibitor.

9. The method of claim 3, wherein the KRAS inhibitor is a KRAS Q61 inhibitor.

10. The method of claim 9, wherein the KRAS Q61 inhibitor is a KRAS Q61K or KRAS Q61H inhibitor.

11. The method of claim 10, wherein the KRAS Q61 inhibitor is a KRAS Q61K inhibitor.

12. The method of claim 10, wherein the KRAS Q61 inhibitor is a KRAS Q61H inhibitor.

13. 3. The method of claim 1 or 2, wherein the KRAS targeted therapy is a bispecific KRAS targeted degrader.

14. The method of claim 1 or 2, wherein the KRAS targeted therapy is an mRNA vaccine targeting KRAS mutant cancer.

15. The KRAS targeted therapy 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

16. The KRAS targeted therapy 【Chemistry 3】 or a pharmaceutically acceptable salt thereof.

17. The KRAS targeted therapy 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

18. 18. The method of any one of claims 1 to 17, wherein the cancer is a SMARCA4-deficient cancer.

19. Such cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma and Schwannoma; 19. The method of any one of claims 1 to 18, wherein the cancer is selected from the group consisting of intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma; T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, B-cell precursor ALL, B-cell precursor lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

20. 20. The method of claim 19, wherein the lung cancer is small cell lung cancer or non-small cell lung cancer.

21. 21. The method of claim 19 or 20, wherein the lung cancer is squamous or non-squamous non-small cell lung cancer, adenocarcinoma, or large cell carcinoma.

22. 20. The method of any one of claims 1 to 19, wherein the cancer is breast cancer, pancreatic cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, lung squamous cell carcinoma, head and neck squamous cell carcinoma, esophageal cancer, gastric cancer, colon adenocarcinoma, bladder cancer, uterine adenocarcinoma, endometrioid adenocarcinoma, skin cancer, melanoma, or lung adenocarcinoma.

23. 20. The method of any one of claims 1 to 19, wherein the cancer is non-small cell lung cancer.

24. 20. The method of any one of claims 1 to 19, wherein the cancer is uterine adenocarcinoma.

25. 20. The method of any one of claims 1 to 19, wherein the cancer is endometrioid adenocarcinoma.

26. 20. The method of any one of claims 1 to 19, wherein the cancer is colon adenocarcinoma.

27. 20. The method of any one of claims 1 to 19, wherein the cancer is ovarian cancer.

28. 28. The method of any one of claims 1 to 27, wherein the amount of the SMARCA2 degrading agent administered to the subject is from about 1 mg / kg to about 50 mg / kg.

29. 29. The method of any one of claims 1 to 28, wherein the amount of the KRAS targeted therapy administered to the subject is from about 1 mg / kg to about 50 mg / kg.

30. The SMARCA2 degrading agent is 【Chemistry 5】 or a pharmaceutically acceptable salt thereof; The KRAS targeted therapy 【Chemistry 6】 30. The method of any one of claims 1 to 29, wherein the compound is a pharmaceutically acceptable salt thereof.

31. The SMARCA2 degrading agent is 【Chemistry 7】 or a pharmaceutically acceptable salt thereof; The KRAS targeted therapy 【Chemistry 8】 30. The method of any one of claims 1 to 29, wherein the compound is a pharmaceutically acceptable salt thereof.

32. A pharmaceutical combination comprising: a SMARCA2 degrading agent or a pharmaceutically acceptable salt thereof; a KRAS targeted therapy or a pharmaceutically acceptable salt thereof; and as a physiologically acceptable excipient.

33. The SMARCA2 degrading agent is 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

34. The KRAS targeted therapy 【Chemistry 10】 or a pharmaceutically acceptable salt thereof.

35. The KRAS targeted therapy 【Chemistry 11】 35. The combination of claim 33 or 34, wherein said compound is a pharmaceutically acceptable salt thereof.

36. The KRAS targeted therapy 【Chemistry 12】 35. The combination of claim 33 or 34, wherein said compound is a pharmaceutically acceptable salt thereof.

37. 37. The combination of any one of claims 33 to 36, wherein the KRAS targeted therapy is a KRAS inhibitor.

38. 38. The combination of claim 37, wherein the KRAS inhibitor is a KRAS G12 inhibitor.

39. 39. The combination of claim 38, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor, a KRAS G12D inhibitor, or a KRAS G12V inhibitor.

40. 40. The combination of claim 39, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor.

41. 40. The combination of claim 39, wherein the KRAS G12 inhibitor is a KRAS G12D inhibitor.

42. 40. The combination of claim 39, wherein the KRAS G12 inhibitor is a KRAS G12V inhibitor.

43. 34. The combination of claim 32 or 33, wherein the KRAS targeted therapy is a KRAS Q61 inhibitor.

44. 44. The combination of claim 43, wherein the KRAS Q61 inhibitor is a KRAS Q61K or KRAS Q61H inhibitor.

45. 45. The combination of claim 44, wherein the KRAS Q61 inhibitor is a KRAS Q61K inhibitor.

46. 45. The combination of claim 44, wherein the KRAS Q61 inhibitor is a KRAS Q61H inhibitor.

47. 34. The combination of claim 32 or 33, wherein the KRAS targeted therapy is a bispecific KRAS targeted degrader.

48. 34. The combination of claim 32 or 33, wherein the KRAS targeted therapy is an mRNA vaccine targeting KRAS mutant cancer.

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