WO2024076985A2

WO2024076985A2 - Improved treatment of cancers using combinations of smarca2 degraders and kras targeting therapies

Info

Publication number: WO2024076985A2
Application number: PCT/US2023/075827
Authority: WO
Inventors: Koichi Ito; Andrew Combs
Original assignee: Prelude Therapeutics Incorporated
Priority date: 2022-10-03
Filing date: 2023-10-03
Publication date: 2024-04-11
Also published as: IL319991A; AU2023356925A1; WO2024076985A3; MX2025004003A; KR20250073663A; CN120152970A; EP4598920A2

Abstract

Methods of treating SMARCA4-deleted cancer cells using a selective SMARCA2 degrader and a KRAS targeting therapy in a combination therapy is described.

Description

IMPROVED TREATMENT OF CANCERS USING COMBINATIONS OF SMARCA2 DEGRADERS AND KRAS TARGETING THERAPIES

TECHNICAL FIELD

[001] The present invention pertains to the use of combinations of SMARCA2 degraders and KRAS targeting therapies for treating cancer.

BACKGROUND

[002] Cell signaling is frequently dysregulated by gene mutations in cancer cells, resulting in aberrant cell growth and cell proliferation. KRAS is one of the most important oncogenes for cancer cell signaling and it activates RAF/MEK/ERK (MAPK) and PI3K signaling. KRAS gene frequently expresses gain-of-function mutation. G12C (glycine 12 to cysteine) can be found in about 13% of lung cancers, 3% of colorectal cancers, and less frequently in uterus, pancreas, breast, bladder, and ovarian cancers. Selective small molecule covalent inhibitors for KRAS G12C mutant have been developed by others and demonstrated promising clinical outcomes (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 remain unfortunate incidences of tumor recurrence after treatment with KRAS G12C inhibitors. Known mechanisms for recurrence and resistance to KRAS G12C inhibitors include bypassing KRAS G12C mutation (i.e., express other mutations within KRAS gene or within other oncogenes) and reactivating the cell signaling (Awad et al. “Acquired Resistance to KRASG12C Inhibition in Cancer” N. Engl. J .Med. (2021) 384: 2382-2393). Therefore, there is a significant need to identify novel therapeutic strategies to delay and overcome such acquired resistance to KRAS G12C inhibitors.

[003] SMARCA4 is a subunit of mammalian S Witch/ Sucrose Non -Fermentable (mSWESNF) complexes which play an important role in controlling gene expression by remodeling chromatin. Cancer cells that express SMARCA4 -deletion mutation are dependent on its paralog gene SMARCA2 for their survival. [004] Combinations of KRAS targeting therapies and SMARCA2 degraders have not been previously described.

SUMMARY

[005] The disclosure provides methods of treating cancer, for example, a 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 targeting therapy, or a pharmaceutically acceptable salt thereof. The described combination therapy is safer and/or more effective in treating the cancer as compared to either the SMARCA2 degrader or the KRAS targeting therapy, alone.

BRIEF DESCRIPTION OF THE DRAWINGS

[006] The foregoing summary, as well as the following detailed description, will be better understood when read in conjunction with the appended drawings, which show exemplary embodiments for the purposes of illustration.

[007] Fig. 1. Percentage of SMARCA4 mutation and KRAS mutation occurrence in total non-small cell lung cancer patient cohort (AACR Project GENIE Consortium). SMARCA4 damaging mutation and gene deletion frequently co-occur with KRAS G12C mutations in non-small cell lung cancer patients.

[008] Fig. 2. Combination of compound 1 and KRAS G12C inhibitor shows synergistic anti-proliferation effects in lung cancer cells (NCI-H2030). Lung cancer NCI-H2030 cells (SMARAC4 low/KRAS G12C) were treated with KRAS G12C inhibitor (MRTX849, AMG510, ARS1629 or JDQ-443) and with a SMARCA2 degrader (compound 1) in a different dose-range. Cell viability was analyzed on day 7 using Cell-titer Gio.

[009] Fig. 3. Combination of compound 1 and KRAS G12C inhibitor shows synergistic anti-proliferation effects in bladder cancer cells (UM-UC-3). Bladder cancer UM-UC-3 cells (SMARAC4 damaging mutation/KRAS G12C) were treated with KRAS G12C inhibitor (MRTX849, AMG510, ARS1629 or JDQ443) and with a SMARCA2 degrader (compound 1) in a different dose-range. Cell viability was analyzed on day 7 using Cell-titer Gio. [010] Fig. 4. Cell lines with no SMARCA4 deletion or KRAS mutation do not show synergistic effects. Lung cancer NCI-H838 cells (SMARAC4 damaging mutation/ KRAS WT) or NCI-H358 cells (SMARCA4 WT/KRAS G12C) were treated with KRAS G12C inhibitor (MRTX849 or AMG510) and with a SMARCA2 degrader (compound 1) in a different dose-range. Cell viability was analyzed on day 7 using Cell-titer Gio.

[Oil] Fig. 5. Bliss and ZIP synergy scores of H2030 cells treated with a SMARCA2 degrader (compound 1) and a KRAS targeting therapy (MRTX849, AMG510, ARS1629 or JDQ443). Synergistic effect is likely where synergy scores are larger than 10 .

[012] Fig. 6. Bliss and ZIP synergy scores of UM-UC-3 cells treated with a SMARCA2 degrader (compound 1) and a KRAS targeting therapy (MRTX849, AMG510, ARS1629 or JDQ443). Synergistic effect is likely where synergy scores are larger than 10.

[013] Fig. 7. Plot of mean tumor volume vs. dosing time for UM-UC-3 cells treated with a SMARCA2 degrader (compound 1) and a KRAS targeting therapy (MRTX849).

[014] Fig. 8. Plot of mean tumor volume vs. dosing time for H2030 cells treated with a SMARCA2 degrader (compound 1) and a KRAS targeting therapy (MRTX849).

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[015] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods which 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, for brevity, described in the context of a single aspect, 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 terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure.

[016] In the present disclosure the singular forms “a,” “an,” and “the” include the plural reference, and 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” is a reference to one or more of such compounds and equivalents thereof known to those skilled in the art, and so forth. The term “plurality”, as used herein, means more than one.

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

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

[019] The term “administering” means either directly administering to the subject a compound, or composition comprising that compound, of the present invention. In other aspects, “administering” refers to administering a prodrug, derivative or analog or a compound of the present invention, which will form an equivalent amount of the compound within the body.

[020] 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.

[021] The terms “patient” and “subject” is used interchangeably throughout the specification to describe an animal, for example, a mammal, to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided. Mammals that can be treated using the methods of the disclosure include rodents such as mice, rats, rabbits, guinea pigs, and the like, as well as domesticated animals such as dogs cats, and farm animals such as a horse, cow, sheep, etc. In other aspects, the mammal is a human.

[022] As employed above and throughout the disclosure the term “therapeutically effective amount” refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result with respect to the treatment of the relevant disorder, condition, or side effect. It will be appreciated that the effective amount of components of the present invention will vary from subject to subject not only with the particular compound, component or composition selected, the route of administration, and the ability of the components to elicit a desired result in the individual, but also with factors such as the disease state or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the state of being of the subject, and the severity of the pathological condition being treated, concurrent medication or special diets then being followed by the particular patient, and other factors which those skilled in the art will recognize. A therapeutically effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeutically beneficial effects.

[023] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans.

[024] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with 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-ethane-disulfonic acid, 2 -hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either 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 such as ethanolamine, diethanolamine, triethanolamine, N-m ethylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.

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

[026] “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating 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, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.

[027] The disclosure is directed to methods of treating cancer in a subject in need thereof. According to these methods, the subject is administered a 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 salt thereof) and the KRAS targeting therapy (or salt thereof) are each administered in amounts that are therapeutically effective in treating the cancer.

[028] The combination therapies described herein are surprising, at least because they show synergistic effects, providing for safer and/or more effective cancer therapy. As used herein, “safer” means that the therapy demonstrates less severe or fewer adverse events or can be administered in lower doses, as compared to a therapy that is not within the scope of the disclosure. As used herein, “more effective” means that the therapy results in a more rapidly observed therapeutic effect or a more significant therapeutic effect, as compared to a therapy that is not within the scope of the disclosure.

[029] As described herein, the administration of a combination therapy comprising the SMARCA2 degrader and the KRAS targeting therapy is safer and/or more effective in treating the subject’s cancer as compared to methods of treating a subject’s cancer by administering the SMARCA2 degrader without the KRAS targeting therapy. Also, or alternatively, the administration of a combination therapy comprising the SMARCA2 degrader and the KRAS targeting therapy is safer and/or more effective in treating the subject’s cancer as compared to methods of treating a subject’s cancer by administering the KRAS targeting therapy without the SMARCA2 degrader.

[030] In other embodiments, the administration of a combination therapy comprising the SMARCA2 degrader and the KRAS targeting therapy is safer and/or more effective in treating the subject’s cancer as compared to methods of treating a subject’s cancer that comprise administering the SMARCA2 degrader but do not comprise administering the KRAS targeting therapy. Also, or alternatively, the administration of a combination therapy comprising the SMARCA2 degrader and the KRAS targeting therapy is safer and/or more effective in treating the subject’s cancer as compared to methods of treating a subject’s cancer that comprise administering the KRAS targeting therapy but do not comprise administering the SMARCA2 degrader.

[031] The synergistic effects of the combination therapy of the disclosure provides for cancer treatments that are safer and/or more effective than existing cancer treatments.

[032] For example, the synergistic effects of administering a described combination therapy can be attained when the compounds of the disclosure are administered together in a single unit dosage form. Alternatively, the synergistic effects of administering a described combination therapy can be attained when the SMARCA2 degrader and the KRAS targeting therapy are each administered as their own separate unit dosage forms. According to these aspects, the SMARCA2 degrader and the KRAS targeting therapy may be administered to the subject at approximately the same time. In other of these aspects, SMARCA2 degrader and the KRAS targeting therapy may be administered at different times, for example, at different times of day or on different days.

[033] According to the disclosure, the SMARCA2 degrader can be any SMARCA2 degrader known in the art. According to the disclosure, “SMARCA2 degraders” include small molecules, for example, those molecules having a molecular weight of less than or equal to 1000 g/mol in free base form. According to the disclosure, these SMARCA2 degraders induce SMARCA2 degradation, resulting in reduced SMARCA2 protein levels in cells and inhibited proliferation of SMARCA4 deficient cancer cells. Preferably SMARCA2 degraders are small molecules that induce >50% of SMARCA2 protein reduction in cells as detected by Western blot, ELISA, HiBiT degradation assay, or any other methods used in the art to detect protein levels. Exemplary SMARCA2 degraders are described in W02022099117A1 and are those molecules that induce >50% of SMARCA2 protein reduction in cells detected by HiBiT degradation assay. The SMARCA2 degraders of use in the described methods can be administered via any suitable route of administration, including orally, subcutaneously, or intravenously.

[034] SMARCA2 degraders useful in the methods of the disclosure include those described in, for example, PCT Application No. W02022099117 and US provisional applications US63/280,205, US63/280,206, US63/318,984, US63/320,573, US63/320,597, US63/340,185, are US63/344,901, the disclosures of each of which are incorporated by reference herein. [035] In certain aspects, the SMARCA2 degrader is Compound 1 :

Compound 1

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

[037] According to the disclosure, the KRAS targeting therapy can be any KRAS targeting therapy known in the art. According to the disclosure, a KRAS targeting therapy can include mRNA vaccines targeting KRAS mutant cancers. Also, according to the disclosure, the KRAS targeting therapy is a KRAS targeting small molecule, for example, a small molecule inhibitor or a bispecific degraders (see, e.g., the targeted protein degraders described in Miklos Bekes, PROTAC targeted protein degraders: the past is prologue, Nature Reviews Drug Discovery, volume 21, pages 181-200 (2022). Small molecule KRAS targeting therapies are those molecules having a molecular weight of less than 1000 g/mol in free base form.

[038] According to the disclosure, a KRAS targeting therapy useful in the described methods is a “KRAS inhibitor.” As used herein, a KRAS inhibitor is a compound that inhibits the biological activity of the KRAS^G12C mutant protein while sparing KRAS wild-type protein, an observation supported by the selectively inhibition of growth of cancer cell lines expressing KRAS^G12C. See Albert Kwan, The path to the clinic: a comprehensive review on direct KRASG12C inhibitors, Journal of Experimental & Clinical Cancer Research, volume 41, 2022. According to the disclosure, mRNA vaccines are mRNA-derived KRAS targeted vaccines, for example, mRNA 5671 vaccine as described in www.cancer.gov/publications/dictionaries/cancer-drug/def/mma-derived-kras-targeted- vaccine-v941. Also within the disclosure are lipid nanoparticle (LNP)-formulated mRNA- based cancer vaccines that target four of the most commonly occurring KRAS mutations (G12D, G12V, G13D, and G12C), with potential immunostimulatory and antineoplastic activities.

[039] The KRAS targeting therapies of use in the described methods can be administered via any suitable route of administration, including orally, subcutaneously, or intravenously. [040] In some aspects of the disclosure, the KRAS targeting therapy is a KRAS G12 inhibitor, for example, a KRAS G12C inhibitor, a KRAS G12D inhibitor, a KRAS G12V inhibitor, or a combination thereof. In some aspects, the KRAS targeting therapy is a KRAS Q61 inhibitor, for example, a KRAS Q61K inhibitor, a KRAS Q61H inhibitor, or a combination thereof. In some aspects, the KRAS targeting therapy is a bispecific KRAS targeting degrader. In some aspects, the KRAS targeting therapy is a mRNA vaccine targeting KRAS mutant cancer.

[041] In certain aspects, the KRAS targeting therapy is adagrasib (MRTX849), sotorasib (AMG510), JDQ443, or a combination thereof:

adagrasib sotorasib

[042] In some aspects of the disclosure the SMARCA2 degrader used in the combination is compound 1 and the KRAS targeting therapy is adagrasib (MRTX849).

[043] In some aspects of the disclosure the SMARCA2 degrader used in the combination is compound 1 and the KRAS targeting therapy is sotorasib.

[044] In some aspects of the disclosure the SMARCA2 degrader used in the combination is compound 1 and the KRAS targeting therapy is JDQ444.

[045] The disclosed combination therapies are useful in treating or preventing a disease or a disorder mediated by SWI/SNF mutations.

[046] The disclosed combination therapies are of use in treating cancer, for example, SMARCA4-deleted cancers. SMARCA4 -del eted cancers can be identified using methods known to those in the art.

[047] In some aspects, the cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which 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, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

[048] In some aspects, the cancer is lung cancer, for example, 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, for example, adenocarcinoma, or largecell carcinoma.

[049] In some aspects, 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.

[050] In some aspects, the cancer is uterine adenocarcinoma.

[051] In certain embodiments, target proteins are SMARCA2, SMARCA4 and/or PB1. [052] In certain embodiments, the target protein complex is SWI/SNF in a cell.

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

[054] In certain embodiments, the present invention provides a pharmaceutical composition for use in the diseases or disorders dependent upon SMARCA2 and/or SMARCA4 is cancer.

Pharmaceutical Compositions Useful in the Described Methods [055] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where desired, the pharmaceutical compositions contain pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[056] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.

[057] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions 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 in the range defined by and including any two numbers above) w/w, w/v or v/v.

[058] In some embodiments, the concentration of one or more compounds of the 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 in the range defined by and including any two numbers above) w/w, w/v, or v/v.

[059] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.

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

[061] In some embodiments, the amount of one or more compounds of the 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 in the range defined by and including any two numbers above).

[062] In some embodiments, the amount of one or more compounds of the invention is more 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, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range defined by and including any two numbers above).

[063] In some embodiments, the amount of one or more compounds of the 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.

[064] A pharmaceutical composition of the invention typically contains an active ingredient (e.g., a compound of the disclosure) of the present invention 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 solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

Pharmaceutical compositions for oral administration.

[065] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration.

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

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

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

[069] In some embodiments, a dose of a KRAS targeting therapy is administered to a subject and a dose of SMARCA2 degrader is administered to the subject. In some embodiments, the KRAS targeting therapy and SMARCA2 degrader are co-administered. [070] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the 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.

[071] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in 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 of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[072] This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the 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 invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[073] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

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

[075] Examples of suitable fillers 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, pre-gelatinized starch, and mixtures thereof.

[076] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may 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-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[077] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the 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 oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition. [078] When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[079] The tablets can be uncoated or 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, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.

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

[081] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (" HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.

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

[083] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

[084] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; 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.

[085] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP - phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl -2 -lacty late, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[086] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids 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 transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with 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 saccharide.

[087] Other hydrophilic-non-ionic surfactants include, without limitation, 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 di oleate, 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 com oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl- 10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, 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 mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[088] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids 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 mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[089] In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion. [090] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols 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, s-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl tri ethyl citrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, s-caprolactone and isomers thereof, 5- valerolactone and isomers thereof, P -butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[091] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methyl- pyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, 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.

[092] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, 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 may also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight. [093] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[094] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tri s(hydroxymethyl)aminom ethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, 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, parabromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic 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. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[095] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic 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 acids, 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 and the like.

Pharmaceutical compositions for injection

[096] In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

[097] The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[098] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[099] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the 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, certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0100] Administration of the compounds or pharmaceutical composition of the present invention can be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally.

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

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

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

[0104] Compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered to treat any of the described diseases, alone or in combination with a medical therapy. Medical therapies include, for example, surgery and radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes).

[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 may further include 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 a medical therapy such as surgery or radiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes.

[0107] Nothing in this specification should be considered as limiting the scope of this disclosure. All examples presented are representative and non-limiting. The above-described embodiments can be modified or varied, as appreciated 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 can be practiced otherwise than as specifically described. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

[0108] The 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 comprising: a therapeutically effective amount of a SMARCA2 degrader or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a KRAS targeting therapy or a pharmaceutically acceptable salt thereof; wherein the administration of the combination therapy is safer and/or more effective in treating the subject’s cancer as compared to treating cancer in a subject in need thereof by: administering the SMARCA2 degrader without the KRAS targeting therapy; administering the KRAS targeting therapy without the SMARCA2 degrader; or a combination thereof.

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

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

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

[0112] 5. The method of 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 of aspect 5, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor.

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

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

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

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

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

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

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

[0121] 14. The method of any of aspects 1-2, wherein the KRAS targeting therapy is a mRNA vaccines targeting KRAS mutant cancer.

[0122] 15. The method of any of aspects 1-2, wherein the KRAS targeting therapy is

(adagrasib),

or a pharmaceutically acceptable salt thereof.

[0123] 16. The method of any of aspects 1-2, wherein the KRAS targeting therapy is

(adagrasib) or a pharmaceutically acceptable salt thereof.

[0124] 17. The method of any of aspects 1-2, wherein the KRAS targeting therapy is

(sotorasib) or a pharmaceutically acceptable salt thereof.

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

[0126] 19. The method of any one of aspects 1-18, wherein the cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which 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, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts 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 nonsmall-cell lung cancer or non-squamous non-small-cell lung cancer, for example, 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 1-19, wherein the cancer is non-small cell lung cancer.

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

[0132] 25. The method of any one of aspects 1-19, 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 1-19, wherein the cancer is ovarian cancer.

[0135] 28. The method of any one of aspects 1-27, wherein the amount of the SMARCA2 degrader 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 the KRAS targeting therapy administered is from about 1 mg/kg to about 50 mg/kg to the subject.

[0137] 30. The method of any one of aspects 1-29, wherein the SMARCA2 degrader is:

or a pharmaceutically acceptable salt thereof; and the KRAS targeting therapy is

or a pharmaceutically acceptable salt thereof.

[0138] 31. The method of any one of aspects 1-29, wherein the SMARCA2 degrader is:

(sotorasib) or a pharmaceutically acceptable salt thereof.

[0139] 32. A pharmaceutical combination comprising: a SMARCA2 degrader or a pharmaceutically acceptable salt thereof; a KRAS targeting therapy or a pharmaceutically acceptable salt thereof; and as pharmaceutically acceptable excipient.

[0140] 33. The combination of aspect 32, wherein the SMARCA2 degrader is:

or a pharmaceutically acceptable salt thereof.

[0141] 34. The combination of any of aspects 32-33, wherein the KRAS targeting therapy

or a pharmaceutically acceptable salt thereof.

[0142] 35. The combination of any of aspects 33-34, wherein the KRAS targeting therapy

(adagrasib) or a pharmaceutically acceptable salt thereof.

[0143] 36. The combination of any of aspects 33-34, wherein the KRAS targeting therapy

(sotorasib) or a pharmaceutically acceptable salt thereof.

[0144] 37. The combination of any of aspects 33-36, wherein the KRAS targeting therapy is a KRAS inhibitor.

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

[0146] 39. The combination of 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 of aspect 39, wherein the KRAS G12 inhibitor is a KRAS G12C inhibitor.

[0148] 41. The combination of aspect 39, wherein the KRAS G12 inhibitor is a KRAS G12D inhibitor.

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

[0150] 43. The combination of any of aspects 33-36, wherein the KRAS targeting therapy is a KRAS Q61 inhibitor. [0151] 44. The combination of aspect 43, wherein the KRAS Q61 inhibitor is a KRAS Q61K or a KRAS Q61H inhibitor.

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

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

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

[0155] 48. The combination of any of aspects 33-36, wherein the KRAS targeting therapy is a mRNA vaccines targeting KRAS mutant cancer.

EXAMPLES

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

[0157] The Bliss independence model assumes a stochastic process in which two drugs elicit their effects independently, and the expected combination effect can be calculated based on the probability of independent events; The ZIP model captures the drug interaction relationships by comparing the change in the potency (effect at certain dose level) of the dose-response curves between individual drugs and their combinations. ZIP assumes that two non-interacting drugs are expected to incur 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: Cells were plated in 384-well white-walled, clear-bottom plates in standard tissue culture conditions. 250 cells per well of the NCI-H2030 (ATCC, CRL-5914) cell line was seeded in RPMI-1640 medium, FBS serum to a final concentration of 10%. 100 cells per well of the UM-UC-3 (ATCC, CRL-1749) cell line was seeded in EMEM medium, FBS serum to a final concentration of 10%. The day after plating, serial dilutions of two compounds were plated in dose-response matrices in quadruplicate, including DMSO controls, using a Tecan D300e Digital Dispenser (Tecan Group Ltd. Mannedorf, Switzerland). All wells were normalized to highest total volume of DMSO. 7 days later the CellTiter-Glo® 2.0 Cell Viability Assay (CTG) (#G9242, Promega, Madison, WI) was used to measure cell viability effects of drug combinations. The expected drug combination responses were calculated based on Bliss and ZIP reference model using SynergyFinder (lanevski et al, 2020). Deviations between observed and expected responses with positive and negative values denote synergy and antagonism respectively. The Bliss and ZIP scores are summarized in Figure 5 and Figure 6. Synergistic effect is likely where synergy scores are larger than 10. MRTX849 (Adagrasib, Catalog No. S8884) and ARS-1620 (Catalog No. S8707) were purchased from Selleck Chemicals. AMG510 (Sotorasib, Catalog No. HY-114277) and JDQ-443 (Catalog No. HY-139612) were purchased from MedChemExpress.

Example 1

[0159] Excellent synergy was observed with compound 1 and KRAS G12C inhibitor (MRTX849, AMG510, ARS-1620 or JDQ-443) in a lung cancer cell line (NCLH2030). NCI- 142030 is a non-small cell lung cancer cell line that express low SMARCA4 and KRAS G12C mutation. Combination therapy was applied to H2030 cells and % viable cells was calculated (see Figure 2). Bliss and ZIP scores are larger than 10, which indicates compound 1 and KRAS G12C inhibitors will likely show synergistic effects (Figure 5).

Example 2

[0160] Excellent synergy also was observed in urinary bladder cancer cell line (UM-UC-3). UC-UM-3 is a human bladder transitional cell carcinoma cancer cell line that expresses SMARCA4 damaging mutation and KRAS G12C mutation. Combination therapy was applied to UM-UC-3 cells and % viable cells was calculated (Figure 3). Bliss and ZIP scores are larger than 10, which indicates compound 1 and KRAS G12C inhibitors will likely show synergistic effects (Figure 6).

[0161] These results show that the combination therapy of SMARCA2 protein degrader compound 1 and a KRAS targeting therapy displays a potent synergistic interaction in SMARCA4 deleted and KRAS G12C mutation expressing cell lines in vitro. Example 3

[0162] Excellent synergy also was observed in urinary bladder cancer cell line (UM-UC-3) with respect to tumor volume reduction. Combination therapy applied to UM-UC-3 cells showed synergistic effects for tumor volume reduction, as shown in FIG. 7. The concentration of compound 1 was 100 mg/kg s.c. Q3D and the concentration of MRTX849 was 10 mg/kg p.o. QD. Statistical analysis used the two-tailed Mann-Whitney test versus vehicle, with *P < 0.05, **P < 0.01 and ***P < 0.001.

[0163] These results show that the combination therapy of SMARCA2 protein degrader compound 1 and a KRAS targeting therapy can slow down the enlargement of tumor volumes. Combination therapy applied to mice with UM-UC-3 xenograft tumors showed synergistic effects for tumor volume reduction.

[0164] Further, FIG. 4 shows two control lines, H838 and H358. H838 does not have a KRAS G12C mutation and FI358 does not have a SMARCA4 mutation. No synergy was observed. Thus, synergy is observed only in cancer cells with both SMARCA4 mutation and KRAS G12C mutation.

Example 4

[0165] Excellent synergy also was observed in lung cancer cell line (NCI-H2030) with respect to tumor volume reduction. Combination therapy applied to H2030 cells showed synergistic effects for tumor volume reduction, as shown in FIG. 8. The concentration of compound 1 was 100 mg/kg s.c. Q3D and the concentration of MRTX849 was 10 mg/kg p.o. QD. Statistical analysis used the two-tailed Mann-Whitney test versus vehicle, with *P < 0.05, **P < 0.01 and ***P < 0.001.

[0166] These results show that the combination therapy of SMARCA2 protein degrader compound 1 and a KRAS targeting therapy can slow down the enlargement of tumor volumes. Combination therapy applied to mice with H2030 xenograft tumors showed synergistic effects for tumor volume reduction.

Claims

What is claimed is:

1. A method of treating cancer in a subject in need thereof 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 targeting therapy or a pharmaceutically acceptable salt thereof; wherein the administration of the combination therapy is safer and/or more effective in treating the subject’s cancer as compared to treating cancer in a subject in need thereof by: administering the SMARCA2 degrader without the KRAS targeting therapy; or administering the KRAS targeting therapy without the SMARCA2 degrader.

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

Compound 1.

3. The method of any one of claims 1-2, wherein the KRAS targeting 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 a

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. The method of any one of claims 1-2, wherein the KRAS targeting therapy is a bispecific KRAS targeting degrader.

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

15. The method of any one of claims 1-2, wherein the KRAS targeting therapy is

or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1-2, wherein the KRAS targeting therapy is

(adagrasib) or a pharmaceutically acceptable salt thereof.

17. The method of any one of claims 1-2, wherein the KRAS targeting therapy is

(sotorasib) or a pharmaceutically acceptable salt thereof.

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

19. The method of any one of claims 1-18, wherein the cancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas, T-lineage Acute lymphoblastic Leukemia (T-ALL), T- lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B- cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.

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

21. The method of 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 of any one of claims 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.

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

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

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

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

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

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

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

30. The method of any one of claims 1-29, wherein the SMARCA2 degrader is:

or a pharmaceutically acceptable salt thereof.

31. The method of any one of claims 1-29, wherein the SMARCA2 degrader is:

(sotorasib) or a pharmaceutically acceptable salt thereof.

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

33. The combination of claim 32, wherein the SMARCA2 degrader is:

or a pharmaceutically acceptable salt thereof.

34. The combination of any one of claims 32-33, wherein the KRAS targeting therapy is

or a pharmaceutically acceptable salt thereof.

35. The combination of any one of claims 33-34, wherein the KRAS targeting therapy is

(adagrasib) or a pharmaceutically acceptable salt thereof.

36. The combination of any one of claims 33-34, wherein the KRAS targeting therapy is

(sotorasib) or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

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

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

48. The combination of any one of claims 32-33, wherein the KRAS targeting therapy is a mRNA vaccine targeting KRAS mutant cancer.