Cancer treatment achieved using combination of SMARCA2 degrading agent and KRAS targeted therapy

Abstract

Methods of treating SMARCA4 deficient cancer cells using a selective SMARCA2 degrading agent and a KRAS targeted therapy in a combination therapy are described.

Description

Technical Field

[0001] The present invention relates to the use of a combination of a SMARCA2 degrader and a KRAS-targeted therapy for the treatment of cancer. Background Art

[0002] Genetic mutations in cancer cells often dysregulate cell signaling, leading to abnormal cell growth and proliferation. KRAS is one of the most important oncogenes in cancer cell signaling and activates the RAF / MEK / ERK (MAPK) and PI3K signaling pathways. The KRAS gene frequently expresses gain-of-function mutations. The G12C (glycine to cysteine mutation at position 12) can be found in approximately 13% of lung cancers, 3% of colorectal cancers, and less commonly, uterine, pancreatic, breast, bladder, and ovarian cancers. Selective small molecule covalent inhibitors of the KRAS G12C mutant 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 KRAS G12C Mutation” N. Engl. J. Med. (2022) 387: 120-131). However, the incidence of tumor recurrence remains high after treatment with KRAS G12C inhibitors. Known mechanisms of recurrence and resistance to KRAS G12C inhibitors include bypassing the KRAS G12C mutation (i.e., expressing other mutations within the KRAS gene or other oncogenes) and reactivation of cell signaling (Awad et al. “Acquired Resistance to KRAS G12C Inhibition in Cancer” N. Engl. J. Med. (2021) 384: 2382-2393). Therefore, there is a need to identify novel therapeutic strategies to delay and overcome this acquired resistance to KRAS G12C inhibitors.

[0003] SMARCA4 is a subunit of the mammalian SWItch / sucrose non-fermentable (mSWI / SNF) complex, which plays an important role in controlling gene expression by remodeling chromatin. Cancer cells expressing SMARCA4 deletion mutants rely on the survival of its paralogous gene SMARCA2.

[0004] The combination of a KRAS-targeted therapy and a SMARCA2 degrader has not been previously described. SUMMARY OF THE INVENTION

[0005] The present disclosure provides a method of treating cancer (e.g., SMARCA4-mutated, deleted, or low-expressing cancer) in a subject in need thereof by administering to the subject a therapeutically effective amount of a combination therapy comprising a therapeutically effective amount of a SMARCA2 degrader or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a KRAS-targeted therapy or a pharmaceutically acceptable salt thereof. The described combination therapy is safer and / or more effective in treating cancer compared to the SMARCA2 degrader or the KRAS-targeted therapy alone. BRIEF DESCRIPTION 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 illustrate exemplary embodiments for purposes of illustration.

[0007] Figure 1 . Percentages of SMARCA4 mutations and KRAS mutations in the total non-small cell lung cancer patient cohort (AACR Project GENIE Consortium). Damaging mutations and gene deletions of SMARCA4 frequently co-occur with KRAS G12C mutations in non-small cell lung cancer patients.

[0008] Figure 2 . The combination of Compound 1 and a KRAS G12C inhibitor showed a synergistic anti-proliferative effect in lung cancer cells (NCI-H2030). Lung cancer NCI-H2030 cells (SMARAC4 low / KRAS G12C) were treated with a KRAS G12C inhibitor (MRTX849, AMG510, ARS1629, or JDQ-443) and a SMARCA2 degrader (Compound 1) at different dose ranges. Cell viability was analyzed using Cell-titer Glo on day 7.

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

[0010] Figure 4 . Cell lines without SMARCA4 deletion or KRAS mutation did not show a synergistic effect. Lung cancer NCI - H838 cells (SMARAC4 - damaging mutation / KRAS WT) or NCI - H358 cells (SMARCA4 WT / KRAS G12C) were treated with a KRAS G12C inhibitor (MRTX849 or AMG510) and a SMARCA2 degrader (Compound 1) at different dose ranges. Cell viability was analyzed using Cell - titer Glo on day 7.

[0011] Figure 5 . Bliss and ZIP synergy scores of H2030 cells treated with a SMARCA2 degrader (Compound 1) and a KRAS - targeted therapy (MRTX849, AMG510, ARS1629, or JDQ443). A synergistic effect may occur when the synergy score is greater than 10.

[0012] Figure 6 . Bliss and ZIP synergy scores of UM - UC - 3 cells treated with a SMARCA2 degrader (Compound 1) and a KRAS - targeted therapy (MRTX849, AMG510, ARS1629, or JDQ443). A synergistic effect may occur when the synergy score is greater than 10.

[0013] Figure 7 . Graph of the average tumor volume of UM - UC - 3 cells treated with a SMARCA2 degrader (Compound 1) and a KRAS - targeted therapy (MRTX849) versus the administration time.

[0014] Figure 8 . Graph of the average tumor volume of H2030 cells treated with a SMARCA2 degrader (Compound 1) and a KRAS - targeted therapy (MRTX849) versus the administration time. Detailed implementation

[0015] The present disclosure can be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods described in the context of separate aspects may also be combined in a single aspect to provide. Alternatively, the various features of the disclosed compositions and methods described in the context of a single aspect for the sake of brevity may also be provided separately or in any sub-combination. 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 pertains. The terms used in this specification are only for the purpose of describing particular embodiments and are not intended to limit the present disclosure.

[0016] In the present disclosure, the singular forms "a", "an", and "the" include plural referents, and a reference to a particular numerical value includes at least that particular value unless the context clearly indicates otherwise. Thus, for example, a reference to "a compound" refers to one or more such compounds known to those skilled in the art and their equivalents, and so forth. As used herein, the term "plurality" means more than one.

[0017] Where a range of values is provided, it is understood that each intermediate value between the upper and lower limits of the range (to one-tenth of the unit of the lower limit) and any other stated value or intermediate value within the stated range is encompassed within the present disclosure. The upper and lower limits of these smaller ranges which may independently be included in the smaller ranges are also encompassed within the present disclosure, subject to any specifically excluded limitations within the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of the included limits are also included in the present disclosure.

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

[0019] The term "administer" means directly administering a compound of the present invention or a composition comprising the compound to a subject. In other aspects, "administer" refers to administering a prodrug, derivative, or analogue or compound of the present invention which will form an equivalent amount of the compound in vivo.

[0020] As used herein, the term "stereoisomer" refers to a compound having the same chemical composition but a different arrangement of atoms or groups in space, for example, 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 a treatment with a composition according to the present disclosure is provided, including prophylactic treatment. Mammals that can be treated using the methods of the present disclosure include rodents such as mice, rats, rabbits, guinea pigs, etc., as well as domestic animals such as dogs and cats, and farm animals such as horses, cows, sheep, etc. In other aspects, the mammal is a human.

[0022] As used above and throughout the present disclosure, the term "therapeutically effective amount" means an effective amount that achieves a desired result with respect to a treatment-related disorder, condition, or side effect at a necessary dose and for a necessary period of time. It will be understood that the effective amount of the components of the present invention will vary from subject to subject and will depend not only on the particular compound, component, or composition selected, the route of administration, and the ability of the component to elicit the desired result in an individual, but also on factors such as the disease state or severity of the condition to be alleviated, hormonal levels, age, gender, individual body weight, the status of the subject, and the severity of the pathological condition being treated, concurrent medications or special diets subsequently followed by the particular patient, and other factors that will be recognized by those skilled in the art. A therapeutically effective amount is also an amount where the therapeutic beneficial effects of the component exceed any toxic or detrimental effects.

[0023] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a State government or corresponding agency in a country other than the United States, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals (e.g., in humans).

[0024] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed from 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, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth ions or aluminum ions); or coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc. By way of example only, the salts further include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains basic functional groups, include salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc.

[0025] "Pharmaceutically acceptable excipients" refer to non-toxic, biologically tolerable and otherwise biologically suitable substances for administration to a subject, such as inert substances, that are added to a pharmacological composition or otherwise used as an agent, carrier or diluent to facilitate the administration of a medicament and are compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol. See, e.g., Remington, J. P. (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., arresting or reducing the development of at least one clinical symptom of the disease or its clinical symptoms). In another embodiment, "treating" or "treatment" refers to ameliorating at least one physical parameter that may not be discernible by a subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder physically (e.g., stabilizing an indiscernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

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

[0028] The combination therapies described herein are surprising, at least in that they exhibit a synergistic effect, thereby providing a 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 therapies not within the scope of the present disclosure. As used herein, "more effective" means that the therapy produces a more rapidly observed therapeutic effect or a more significant therapeutic effect compared to therapies not within the scope of the present disclosure.

[0029] As described herein, administering a combination therapy comprising a SMARCA2 degrader and a KRAS targeting therapy is safer and / or more effective in treating cancer in a subject compared to a method of treating cancer in a subject by administering a SMARCA2 degrader without a KRAS targeting therapy. Additionally or alternatively, administering a combination therapy comprising a SMARCA2 degrader and a KRAS targeting therapy is safer and / or more effective in treating cancer in a subject compared to a method of treating cancer in a subject by administering a KRAS targeting therapy without a SMARCA2 degrader.

[0030] In other embodiments, compared to methods of treating a subject's cancer that include administering a SMARCA2 degrader but do not include administering a KRAS targeting therapy, administering a combination therapy that includes a SMARCA2 degrader and a KRAS targeting therapy is safer and / or more effective in treating the subject's cancer. Additionally or alternatively, compared to methods of treating a subject's cancer that include administering a KRAS targeting therapy but do not include administering a SMARCA2 degrader, administering a combination therapy that includes a SMARCA2 degrader and a KRAS targeting therapy is safer and / or more effective in treating the subject's cancer.

[0031] The synergistic effect of the combination therapies of the present disclosure provides a safer and / or more effective cancer treatment than existing cancer treatments.

[0032] For example, when the compounds of the present disclosure are administered together in a single unit dosage form, the synergistic effect of administering the described combination therapy can be achieved. Alternatively, when the SMARCA2 degrader and the KRAS targeting therapy are each administered as their separate unit dosage forms, the synergistic effect of administering the described combination therapy can be achieved. In accordance with these aspects, the SMARCA2 degrader and the KRAS targeting therapy can be administered to the subject substantially simultaneously. In other aspects of these aspects, the SMARCA2 degrader and the KRAS targeting therapy can be administered at different times, e.g., at different times of the day or on different dates.

[0033] In accordance with the present disclosure, the SMARCA2 degrader can be any SMARCA2 degrader known in the art. In accordance with the present disclosure, "SMARCA2 degrader" includes small molecules, such as those in free base form having a molecular weight less than or equal to 1000 g / mol. In accordance with the present disclosure, these SMARCA2 degraders induce SMARCA2 degradation, resulting in a decrease in the level of SMARCA2 protein in cells and inhibiting the proliferation of SMARCA4-deficient cancer cells. Preferably, the SMARCA2 degrader is a small molecule that induces a >50% reduction in SMARCA2 protein in cells, as detected by Western blot, ELISA, HiBiT degradation assay, or any other method used in the art to detect protein levels. Exemplary SMARCA2 degraders are described in WO2022099117A1 and are molecules that induce a >50% reduction in SMARCA2 protein in cells as detected by the HiBiT degradation assay. The SMARCA2 degrader used in the described methods can be administered by any suitable route of administration, including oral administration, subcutaneous administration, or intravenous administration.

[0034] SMARCA2 degraders that can be used in the methods of the present disclosure include, for example, those described in PCT application number WO2022099117 and US Provisional Applications US63 / 280,205, US63 / 280,206, US63 / 318,984, US63 / 320,573, US63 / 320,597, US63 / 340,185, and US63 / 344,901, the disclosures of each of which are incorporated herein by reference.

[0035] In certain aspects, the SMARCA2 degrader is Compound 1: 。

[0036] Stereoisomers of Compound 1 are also suitable for 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 mRNA vaccines targeting KRAS mutant cancers. Additionally, 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, e.g., targeted protein degraders described in the following literature: Miklós Békés, PROTAC Targeted Protein Degraders: The Past is Prologue, Nature Reviews Drug Discovery, Volume 21, Pages 181-200 (2022)). The small molecule KRAS-targeted therapy is a molecule in free base form with a molecular weight less than 1000 g / mol.

[0038] According to the present disclosure, the KRAS-targeted therapy that can be used in the described methods is a "KRAS inhibitor". As used herein, a KRAS inhibitor is a compound that inhibits the G12C KRAS mutant protein while retaining the biological activity of the KRAS wild-type protein, an observation that is supported by selectively inhibiting the expression of KRAS G12CSupport for the growth of cancer cell lines. See Albert Kwan, The path to the clinic: a comprehensive review on direct KRASG12C inhibitors, Journal of Experimental & Clinical Cancer Research, Vol. 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 within the present disclosure are lipid nanoparticle (LNP)-formulated mRNA-based cancer vaccines that target the four most common KRAS mutations (G12D, G12V, G13D, and G12C) and have potential immunostimulatory and anti-tumor activity.

[0039] The KRAS-targeted therapy used in the described methods can be administered by any suitable route of administration, including oral administration, subcutaneous administration, or intravenous administration.

[0040] In some aspects of the present disclosure, the KRAS-targeted therapy is a KRAS G12 inhibitor, such as a KRAS G12C inhibitor, a KRAS G12D inhibitor, a KRAS G12V inhibitor, or a combination thereof. In some aspects, the KRAS-targeted therapy is a KRAS Q61 inhibitor, such as a KRAS Q61K inhibitor, a KRAS Q61H inhibitor, or a combination thereof. In some aspects, the KRAS-targeted therapy is a bispecific KRAS-targeted degrader. In some aspects, the KRAS-targeted therapy is an mRNA vaccine targeting KRAS mutant cancers.

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

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

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

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

[0045] The disclosed combination therapy can be used to treat or prevent diseases or disorders mediated by SWI / SNF mutations.

[0046] The disclosed combination therapy is used to treat cancer, such as cancers lacking SMARCA4. Cancers lacking SMARCA4 can be identified using methods known to those of skill in the art.

[0047] In some aspects, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, rhabdomyosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineocytoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; bowel 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 can be treated with the 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, precursor B ALL, precursor B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL and Philadelphia chromosome-positive CML.

[0048] In some aspects, the cancer is lung cancer, such as small cell lung cancer or non-small cell lung cancer. In some aspects, 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.

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

[0050] In some aspects, 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 the cell.

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

[0054] In certain embodiments, the present invention provides a pharmaceutical composition for a disease or disorder that is dependent on SMARCA2 and / or SMARCA4, which is cancer. Pharmaceutical compositions useful for the described methods

[0055] The subject pharmaceutical composition is generally formulated to provide a therapeutically effective amount of the compounds of the present disclosure in the form of an active ingredient or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. When needed, the pharmaceutical composition contains its pharmaceutically acceptable salts and / or coordination complexes and 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] The subject pharmaceutical composition can be administered alone or in combination with one or more other agents, which are also generally administered in the form of a pharmaceutical composition. When needed, one or more compounds of the present invention and the other agents can be mixed into a preparation, or the two components can be formulated into separate preparations for separate or simultaneous combined use.

[0057] In some embodiments, the concentration of one or more compounds in the pharmaceutical composition of the present invention is less than 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%, 0.005%, 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 the 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 greater than 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%, 0.05%, 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 the range defined by any two of the above numbers 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 in the range of about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% 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 in 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%, 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 equal to or less than 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, 0.02 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 within the 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 greater than 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, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g or 10 g (or a number within the range defined by any two of the above numbers and including any two of the above numbers).

[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] The pharmaceutical composition of the present invention generally contains the active ingredient of the present invention (for example, the compounds disclosed in 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. Pharmaceutical compositions for oral administration 。

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

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

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

[0068] In some embodiments, the pharmaceutical composition for oral administration comprises a KRAS targeting therapy, a SMARCA2 degrader, and a pharmaceutical excipient suitable for oral administration.

[0069] In some embodiments, a subject is administered a dose of a KRAS targeting therapy and a subject is administered a dose of a SMARCA2 degrader. In some embodiments, the KRAS targeting therapy and the SMARCA2 degrader are co-administered.

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

[0071] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical composition of the present invention suitable for oral administration may be presented in discrete dosage forms, such as capsules, cachets or tablets, or liquid or aerosol sprays, solutions, or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions, each containing a predetermined amount of the active ingredient in the form of a powder or granules. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with a carrier, which constitutes one or more essential ingredients. Generally, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired presentation form. For example, tablets can be prepared by compression or molding, optionally with one or more auxiliary 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 can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0072] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms that contain an active ingredient, as water can promote the degradation of some compounds. For example, in the pharmaceutical field, water (e.g., 5%) can be added as a means to simulate long-term storage to determine the characteristics of a formulation over time, such as shelf life or stability. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. If substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage, the pharmaceutical compositions and dosage forms of the present invention containing lactose can be made water-free. The anhydrous pharmaceutical compositions can be prepared and stored in a manner that maintains their anhydrous nature. Thus, the anhydrous compositions can be packaged using materials known to prevent exposure to water, such that the compositions can be included in a suitable prescribed kit. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, etc., unit-dose containers, blister packs, and strip packs.

[0073] According to conventional pharmaceutical compounding techniques, the active ingredient can be intimately mixed with a pharmaceutical carrier. The carrier can take various forms depending on the desired form of preparation for administration. When preparing compositions for oral dosage forms, in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, any common pharmaceutical medium can be used as a carrier, such as water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, coloring agents, etc.; or in the case of oral solid preparations, carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used, and lactose is not used in some embodiments. For example, in the case of solid oral preparations, suitable carriers include powders, capsules, and tablets. 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 arabic, 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, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, 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., in granular or powdered form), 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 upon exposure to an aqueous environment. Too much disintegrant may result in tablets that disintegrate in the bottle. Too little disintegrant may be insufficient to cause disintegration and may thus alter the rate and extent of release of one or more active ingredients from the dosage form. Accordingly, an amount of disintegrant sufficient (not to adversely alter the release of one or more active ingredients by being too little or too much) can be used to form dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary based on the type of formulation and mode of administration and can be readily discerned by one of ordinary skill in the art. About 0.5 to about 15% by weight of disintegrant or about 1 to about 5% by weight of disintegrant can be used in the pharmaceutical composition. Disintegrants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar-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 alginates, 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 diols, 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, synthetic silica gels, coagulated aerosols of synthetic silica, or mixtures thereof. Optionally, the lubricant can be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0078] When an aqueous suspension and / or elixir is required for oral administration, the active ingredient therein can be mixed with various sweetening or flavoring agents, coloring agents or dyes, and (if desired) emulsifying and / or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0079] Tablets can be uncoated or can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, retardation materials such as glyceryl monostearate or glyceryl distearate can be employed. The formulations for oral use can also be presented in the form of hard gelatin capsules or soft gelatin capsules. In the case of hard gelatin capsules, the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin). In the case of soft gelatin capsules, the active ingredient is mixed with a water or oil medium (e.g., 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, mixtures of hydrophilic surfactants can be employed, mixtures of lipophilic surfactants can be employed, or mixtures of at least one hydrophilic surfactant and at least one lipophilic surfactant can be employed.

[0081] The HLB value of suitable hydrophilic surfactants can generally be at least 10, while the HLB value of suitable lipophilic surfactants can generally be or less than about 10. The 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 greater solubility in oil, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions.

[0082] Hydrophilic surfactants are generally considered to be those compounds with 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 with an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide commonly used to achieve the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0083] Hydrophilic surfactants can be ionic or nonionic surfactants. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glycerol ester derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysophosphatidylcholine and hydrogenated lysophosphatidylcholine; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0084] Within the above groups, by way of example, ionic surfactants include lecithin, lysophosphatidylcholine, phospholipids, lysophospholipids, and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0085] Ionic surfactants can be in the following ionized forms: lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactates, stearoyl-2-lactylate, stearoyl lactate, succinylated monoglycerides, mono / diglyceride mono / diacetylated tartrates, mono / diglyceride citrates, cholylsarcosine, caproates, caprylates, caprates, laurates, myristates, palmitates, oleates, ricinoleates, linoleates, linolenates, stearates, lauryl sulfates, myristyl sulfates, dioctyl sulfosuccinates, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and their salts and mixtures.

[0086] Hydrophilic nonionic surfactants can include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; polyethylene glycol glycerol laurates; polyoxyalkylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyalkylene alkyl phenols, such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol 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; hydrophobic transesterification products of polyols having at least one member from the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, their derivatives, and analogs; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; hydrophilic transesterification products of polyethylene glycol sorbitan fatty acid esters and polyols having at least one member from the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or sugar.

[0087] Other hydrophilic nonionic surfactants include, but are not limited to, 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, PEG-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 caprylic / capric glycerides, PEG-8 caprylic / capric glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 stigmasterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 dodecyl ether, POE-23 dodecyl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-oleate, Tween 40, Tween60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

[0088] By way of example only, suitable lipophilic surfactants include: 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; lactic acid derivatives of monoglycerides and diglycerides; hydrophobic transesterification products of polyols having at least one member of the group consisting of glycerol esters, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters and mixtures thereof, or hydrophobic transesterification products of polyols having at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0089] In one embodiment, the composition may include solubilizers to ensure good solubilization and / or dissolution of the compounds of the present invention and to minimize precipitation of the compounds of the present invention. This is particularly important for compositions for non-oral use (e.g., injectable compositions). Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants or to keep the composition as a stable or homogeneous solution or dispersion.

[0090] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols such as ethanol, isopropyl alcohol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, epoxydiol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methyl cellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of from about 200 to about 6000 such as tetrahydrofurfuryl alcohol PEG ether (glycogen) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkyl pyrrolidones, N-hydroxyalkyl pyrrolidones, N-alkyl piperidones, N-alkyl caprolactams, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl acetyl citrate, tributyl acetyl 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 solubilizers known in the art such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monoglyceryl caprylate, diethylene glycol monoethyl ether and water.

[0091] Mixtures of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200 - 100, glycogen, epoxydiol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycogen, 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 bioacceptable amount that can be readily determined by one of ordinary skill in the art. In some cases, it may be advantageous to include a solubilizer in an amount far in excess of the bioacceptable amount, for example, to maximize the concentration of the drug, where the excess solubilizer is removed using conventional techniques such as distillation or evaporation before the composition is administered to a subject. Thus, by weight of the combined weight of the drug and other excipients, the weight ratio of the solubilizer (if present) can be 10 wt%, 25 wt%, 50 wt%, 100 wt%, or > up to about 200 wt%. If desired, very small amounts of solubilizer can also be used, such as > 5%, > 2%, 1% or even less. Typically, the solubilizer can be present in an amount of > about 1 wt% to about 100 wt%, more typically > about 5 wt% to > about 25 wt%.

[0093] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, antiadherents, antifoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavoring agents, coloring agents, flavor enhancers, opacifying agents, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0094] Alternatively, an acid or a base can be incorporated into the composition to facilitate processing, enhance stability, or achieve other purposes. 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, methanesulfonic 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, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic 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 and pharmaceutically acceptable cation such as ammonium, alkali metals, alkaline earth metals, and the like. Examples can 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, and the like. 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, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, toluenesulfonic acid, uric acid, and the like. Pharmaceutical compositions for injection

[0096] In some embodiments, the present invention provides a pharmaceutical composition for injection, which contains a compound of the present invention and a pharmaceutically acceptable excipient suitable for injection. The components and amounts of the medicaments in the composition are as described herein.

[0097] Forms that can be incorporated into the novel compositions of the present invention for administration by injection include aqueous or oil suspensions or emulsions having 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 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. Appropriate fluidity can be maintained, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of a dispersant, and by using surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0099] A sterile injectable solution is prepared by incorporating the compound of the present invention in a required amount, together with various other ingredients enumerated above, into a suitable solvent as needed, and then filtering and sterilizing. Generally, a dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, some desirable preparation methods are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient and any additional desired ingredients from its previously sterile-filtered solution.

[0100] Administration of the compound or pharmaceutical composition of the present invention can be achieved by any method capable of delivering the compound to the site of action. These methods include oral route, duodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intracavitary, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, local delivery via a catheter or stent, or by inhalation. The compound can also be administered intralipally or intrathecally.

[0101] In some embodiments, the compound or pharmaceutical composition of the present invention is administered by intravenous injection.

[0102] The subject pharmaceutical composition can be, for example, in the form suitable for sustained-release formulations, solutions, suspensions, suitable for parenteral injection in the form of a sterile solution, suspension or emulsion, suitable for topical application in the form of an ointment or cream, or suitable for rectal administration in the form of a suppository. The pharmaceutical composition can be in unit dosage form suitable for administering a precise dose in a single administration. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and the compound according to the present invention as the active ingredient. Additionally, the pharmaceutical composition can include other medicinal agents, carriers, adjuvants, etc.

[0103] Exemplary parenteral administration forms include solutions or suspensions of the active compound in a sterile aqueous solution, such as an aqueous solution of propylene glycol or an aqueous solution of glucose. Such dosage forms can be buffered appropriately if needed.

[0104] The compounds of the present disclosure and pharmaceutical compositions comprising the compounds can be administered alone or in combination with medical therapies to treat any of the described diseases. Medical therapies include, for example, surgery and radiation therapy (e.g., γ-radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, systemic radioisotopes).

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

[0106] For treating cancer and other proliferative diseases, the described methods of treatment can further include a combination with other chemotherapeutic agents, agonists or antagonists of nuclear receptors, or other anti-proliferative agents. The described methods can also be used in combination with medical therapies such as surgery or radiation therapy, e.g., γ-radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes.

[0107] Nothing in this specification should be construed as limiting the scope of the present disclosure. All examples presented are representative and non-limiting. As will be understood by those skilled in the art in light of the above teachings, the above embodiments can be modified or changed. Accordingly, it is to be understood that within the scope of the claims and their equivalents, the embodiments disclosed herein can be practiced in a manner different from that specifically described. The disclosures of all patents and scientific literature cited herein are hereby expressly incorporated by reference in their entirety.

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

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

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

[0111] 4. The method according to aspect 3, wherein the KRAS inhibitor is a KRAS G12 inhibitor.

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

[0113] 6. The method according to aspect 5, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor.

[0114] 7. The method according to aspect 5, wherein the KRAS G12 inhibitor is a KRAS G12D inhibitor.

[0115] 8. The method according to aspect 5, wherein the KRAS G12 inhibitor is a KRAS G12V inhibitor.

[0116] 9. The method according to aspect 3, wherein the KRAS inhibitor is a KRAS Q61 inhibitor.

[0117] 10. The method according to aspect 9, wherein the KRAS Q61 inhibitor is a KRAS Q61K or a KRAS Q61H inhibitor.

[0118] 11. The method according to aspect 10, wherein the KRAS Q61 inhibitor is a KRAS Q61K inhibitor.

[0119] 12. The method according to aspect 10, wherein the KRAS Q61 inhibitor is a KRAS Q61H inhibitor.

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

[0121] 14. The method according to any one of aspects 1 to 2, wherein the KRAS-targeted therapy is an mRNA vaccine targeting KRAS mutant cancers.

[0122] 15. The method according to any one of aspects 1 to 2, wherein the KRAS-targeted therapy is (Adagrasib), (Sotorasib), or (JDQ443) or a pharmaceutically acceptable salt thereof.

[0123] 16. The method according to any one of aspects 1 to 2, wherein the KRAS targeting therapy is (Adagrasib) or a pharmaceutically acceptable salt thereof.

[0124] 17. The method according to any one of aspects 1 to 2, wherein the KRAS targeting therapy is (Sotorasib) or a pharmaceutically acceptable salt thereof.

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

[0126] 19. The method according to any one of aspects 1 to 18, wherein the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer; leukemia; benign and malignant lymphoma, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative diseases; sarcoma, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, rhabdomyosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma multiforme, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineocytoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; bowel 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 can be treated with the compounds according to the present disclosure include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-ALL, precursor B-lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL and Philadelphia chromosome-positive CML.

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

[0128] 21. The method according to 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 according to any one of aspects 1 to 19, wherein the cancer is breast cancer, pancreatic cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, squamous cell carcinoma of the head and neck, esophageal cancer, gastric cancer, colorectal adenocarcinoma, bladder cancer, uterine adenocarcinoma, endometrioid adenocarcinoma, skin cancer, melanoma or lung adenocarcinoma.

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

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

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

[0133] 26. The method according to any one of aspects 1 to 19, wherein the cancer is colorectal adenocarcinoma.

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

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

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

[0137] 30. The method according to any one of aspects 1 to 29, wherein the SMARCA2 degrader is: Compound 1; or a pharmaceutically acceptable salt thereof; and the KRAS-targeted therapy is (Adagrasib) or a pharmaceutically acceptable salt thereof.

[0138] 31. The method according to any one of aspects 1 to 29, wherein the SMARCA2 degrader is: Compound 1; or a pharmaceutically acceptable salt thereof; and The KRAS-targeted therapy is (sotorasib) or a pharmaceutically acceptable salt thereof.

[0139] 32. A drug combination comprising: a SMARCA2 degrader or a pharmaceutically acceptable salt thereof; a KRAS-targeted therapy or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0140] 33. The combination according to aspect 32, wherein the SMARCA2 degrader is: Compound 1 or a pharmaceutically acceptable salt thereof.

[0141] 34. The combination according to any one of aspects 32 to 33, wherein the KRAS-targeted therapy is (adagrasib), (sotorasib), or (JDQ443) or a pharmaceutically acceptable salt thereof.

[0142] 35. The combination according to any one of aspects 33 to 34, wherein the KRAS-targeted therapy is (adagrasib) or a pharmaceutically acceptable salt thereof.

[0143] 36. The combination according to any one of aspects 33 to 34, wherein the KRAS-targeted therapy is (sotorasib) or a pharmaceutically acceptable salt thereof.

[0144] 37. The 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. The combination according to aspect 39, wherein the KRAS G12 inhibitor is a KRAS G12D inhibitor.

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

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

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

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

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

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

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

[0156] The degree of combinatorial synergy or antagonism is quantified by comparing the observed drug combination response to the expected response, which is calculated using a reference model assuming no interaction between the drugs. Drug synergy is determined using the Bliss and zero interaction potency (ZIP) reference models. These models quantify the degree of synergy as the multiplicative effect of the single drugs as if they were acting independently (Bliss), or the expected response corresponding to the effect as if the single drugs did not affect each other's potencies (ZIP).

[0157] The Bliss independence model assumes a stochastic process in which two drugs independently elicit their effects, and the expected combined effect can be calculated based on the probabilities of independent events; the ZIP model captures drug interaction relationships by comparing the changes in the potencies (effects at certain dose levels) of the dose-response curves of the individual drugs and their combination. The ZIP assumes that two non-interacting drugs are expected to produce minimal changes in their dose-response curves. Model calculations can be found at www.ncbi.nlm.nih.gov / pmc / articles / PMC4759128 / .

[0158] Cell proliferation assay: Under standard tissue culture conditions, cells were seeded in 384-well white-wall clear bottom plates. The NCI-H2030 (ATCC, CRL-5914) cell line at 250 cells / well was seeded in RPMI-1640 medium with 10% final concentration of FBS serum. The UM-UC-3 (ATCC, CRL-1749) cell line at 100 cells / well was seeded in EMEM medium with 10% final concentration of FBS serum. On the day after seeding, serial dilutions of two compounds were seeded in quadruplicate in a dose-response matrix, including DMSO controls, using a Tecan D300e digital dispenser (Tecan Group Ltd. Männedorf, Switzerland). All wells were normalized to the highest total volume relative to DMSO. After 7 days, the cell viability effects of the drug combinations were measured using the CellTiter-Glo® 2.0 Cell Viability Assay (CTG) (#G9242, Promega, Madison, WI). The expected drug combination responses were calculated using SynergyFinder based on the Bliss and ZIP reference models (Ianevski et al., 2020). Deviations with positive and negative values between the observed and expected responses represent synergistic and antagonistic effects, respectively. The Bliss and ZIP scores are summarized in Figure 5 and Figure 6 . Synergistic effects are likely to occur when the synergistic effect 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. Example 1

[0159] Excellent synergistic effects were observed in the lung cancer cell line (NCI-H2030) with compound 1 and KRAS G12C inhibitors (MRTX849, AMG510, ARS-1620, or JDQ-443). NCI-H2030 is a non-small cell lung cancer cell line expressing low SMARCA4 and KRAS G12C mutations. The combination therapy was applied to H2030 cells, and the % of live cells was calculated (see Figure 2 ). The Bliss and ZIP scores were greater than 10, indicating that compound 1 and KRAS G12C inhibitors would likely show a synergistic effect ( Figure 5 ). Example 2

[0160] Excellent synergistic effects were also observed in the bladder cancer cell line (UM-UC-3). UC-UM-3 is a human bladder transitional cell carcinoma cell line expressing SMARCA4 loss-of-function mutations and KRAS G12C mutations. The combination therapy was applied to UM-UC-3 cells, and the % of live cells was calculated ( Figure 3 ). The Bliss and ZIP scores were greater than 10, indicating that compound 1 and KRAS G12C inhibitors would likely show a synergistic effect ( Figure 6 ).

[0161] These results indicate that the combination therapy of the SMARCA2 protein degrader compound 1 and KRAS-targeted therapy shows effective synergistic interactions in vitro in SMARCA4-deficient and KRAS G12C-mutated cell lines. Example 3

[0162] Regarding tumor volume reduction, excellent synergistic effects were also observed in the bladder cancer cell line (UM-UC-3). The combination therapy applied to UM-UC-3 cells showed a synergistic effect on tumor volume reduction, as Figure 7 shown. The concentration of compound 1 was 100 mg / kg subcutaneously Q3D, and the concentration of MRTX849 was 10 mg / kg orally QD. Statistical analysis was performed using a two-tailed Mann-Whitney test relative to the vehicle, where *P < 0.05, **P < 0.01, and ***P < 0.001.

[0163] These results indicate that the combination therapy of the SMARCA2 protein degrader compound 1 and KRAS-targeted therapy can slow down the expansion of tumor volume. The combination therapy applied to mice with UM-UC-3 xenograft tumors showed a synergistic effect on tumor volume reduction.

[0164] In addition,Figure 4 Two control cell lines, H838 and H358, are shown. H838 does not have the KRAS G12C mutation, while H358 does not have the SMARCA4 mutation. No synergy was observed. Thus, a synergistic effect was only observed in cancer cells with both the SMARCA4 mutation and the KRAS G12C mutation. Example 4

[0165] Regarding tumor volume reduction, excellent synergistic effects were also observed in a lung cancer cell line (NCI-H2030). The combination therapy applied to H2030 cells showed a synergistic effect on tumor volume reduction, as Figure 8 shown. The concentration of Compound 1 was 100 mg / kg subcutaneous Q3D, and the concentration of MRTX849 was 10 mg / kg oral QD. Statistical analysis was performed using a two-tailed Mann-Whitney test relative to vehicle, where *P < 0.05, **P < 0.01 and ***P < 0.001.

[0166] These results indicate that the combination therapy of the SMARCA2 protein degrader Compound 1 and the KRAS-targeted therapy can slow down the expansion of tumor volume. The combination therapy applied to mice with H2030 xenograft tumors showed a synergistic effect on tumor volume reduction.

Claims

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination therapy comprising: A therapeutically effective amount of a SMARCA2 degrader or a pharmaceutically acceptable salt thereof; and A therapeutically effective amount of a KRAS-targeted therapy or a pharmaceutically acceptable salt thereof; Wherein the administration of the combination therapy is safer and / or more effective in treating the cancer of the subject compared to treating the cancer of a subject in need thereof by: Administering the SMARCA2 degrader without the KRAS-targeted therapy; or Administering the KRAS-targeted therapy without the SMARCA2 degrader.

2. The method according to claim 1, wherein the SMARCA2 degrader is compound 1 or a pharmaceutically acceptable salt thereof: Compound 1.

3. The method according to any one of claims 1 to 2, wherein the KRAS-targeted therapy is a KRAS inhibitor.

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

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

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

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

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

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

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

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

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

13. The method according to any one of claims 1 to 2, wherein the KRAS-targeted therapy is a bispecific KRAS-targeted degrader.

14. The method according to any one of claims 1 to 2, wherein the KRAS-targeted therapy is an mRNA vaccine targeting KRAS mutant cancer.

15. The method according to any one of claims 1 to 2, wherein the KRAS-targeted therapy is (Adagrasib), (Sotorasib), or (JDQ443) Or a pharmaceutically acceptable salt thereof.

16. The method according to any one of claims 1 to 2, wherein the KRAS-targeted therapy is (Adagrasib) Or a pharmaceutically acceptable salt thereof.

17. The method according to any one of claims 1 to 2, wherein the KRAS-targeted therapy is (Sotorasib) Or a pharmaceutically acceptable salt thereof.

18. The method according to any one of claims 1 to 17, wherein the cancer is a cancer with SMARCA4 deletion.

19. The method according to any one of claims 1 to 18, wherein the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer; leukemia; benign and malignant lymphoma, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative diseases; sarcoma, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineocytoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; 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, precursor B ALL, precursor B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL and Philadelphia chromosome-positive CML.

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

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

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

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

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

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

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

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

29. The method according to 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 method according to any one of claims 1 to 29, wherein the SMARCA2 degrader is: Compound 1; or a pharmaceutically acceptable salt thereof; and the KRAS-targeted therapy is (Adagrasib) or a pharmaceutically acceptable salt thereof.

31. The method according to any one of claims 1 to 29, wherein the SMARCA2 degrader is: Compound 1; or a pharmaceutically acceptable salt thereof; and the KRAS-targeted therapy is (Sotorasib) or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical combination, comprising: a SMARCA2 degrader or a pharmaceutically acceptable salt thereof; a KRAS-targeted therapy or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

33. The combination according to claim 32, wherein the SMARCA2 degrader is: Compound 1 or a pharmaceutically acceptable salt thereof.

34. The combination according to any one of claims 32 to 33, wherein the KRAS-targeted therapy is (Adagrasib), (Sotorasib), or (JDQ443) or a pharmaceutically acceptable salt thereof.

35. The combination according to any one of claims 33 to 34, wherein the KRAS-targeted therapy is (Adagrasib) or a pharmaceutically acceptable salt thereof.

36. The combination according to any one of claims 33 to 34, wherein the KRAS-targeted therapy is (Sotorasib) or a pharmaceutically acceptable salt thereof.

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

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

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

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

41. The combination according to claim 39, wherein the KRAS G12 inhibitor is a KRAS G12D inhibitor.

42. The combination according to claim 39, wherein the KRAS G12 inhibitor is a KRAS G12V inhibitor.

43. The combination according to any one of claims 32 to 33, wherein the KRAS-targeted therapy is a KRAS Q61 inhibitor.

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

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

46. The combination according to claim 44, wherein the KRAS Q61 inhibitor is a KRAS Q61H inhibitor.

47. The combination according to any one of claims 32 to 33, wherein the KRAS targeting therapy is a bispecific KRAS targeting degrader.

48. The combination according to any one of claims 32 to 33, wherein the KRAS targeting therapy is an mRNA vaccine targeting KRAS mutant cancers.

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