RMC-6291 for use in the treatment of RAS protein-related disorders or disabilities

Abstract

This disclosure features a method for treating RAS disorders using compound (A) or a pharmaceutically acceptable salt thereof. This disclosure also features a method for treating RAS disorders (e.g., cancer) comprising a combination of compound (A) or a pharmaceutically acceptable salt thereof and additional therapeutic agents. Compound (A) is a compound having structure (A). JPEG2026527616000011.jpg48170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Application No. 63 / 531,175 filed on 7 August 2023, U.S. Application No. 63 / 543,420 filed on 10 October 2023, and U.S. Application No. 63 / 618,783 filed on 8 January 2024, all of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Most small molecule drugs act by binding to functionally important pockets on target proteins, thereby modulating the activity of those proteins. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrate. The fact that many such drug / target interaction pairs are known may have led some to believe that, given a reasonable amount of time, effort, and resources, small molecule modifiers could be discovered for most, if not all, proteins. This is far from the truth. Current estimates suggest that only about 10% of all human proteins are targetable by small molecules. The remaining 90% are currently considered refractory or refractory to the small molecule drug discovery described above. Such targets are commonly referred to as "untargetable." These untargetable targets include a vast and largely undeveloped treasure trove of medically important human proteins. Therefore, there is great interest in discovering novel molecular modalities capable of modulating the function of such untargetable targets.

[0003] RAS proteins (KRAS, HRAS, and NRAS) play a crucial role in various human cancers and are therefore well-established targets for anticancer therapy in the literature. In fact, mutations in the RAS protein account for approximately 30% of all human cancers in the United States, many of which are lethal. Dysregulation of the RAS protein due to mutation activation, overexpression, or upstream activation is common in human tumors, and mutation activation in RAS is frequently found in human cancers. For example, activation of a mutation at codon 12 in the RAS protein functions by inhibiting both the GTPase-activated protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly distorting the population of RAS mutant proteins into an "on" (GTP-bound) state (RAS(ON)), leading to oncogenic MAPK signaling. In particular, RAS exhibits picomolar affinity for GTP, allowing RAS to be activated even in the presence of low concentrations of this nucleotide. Mutations in codon 13 of the RAS (e.g., G13C) and in codon 61 (e.g., Q61K) also contribute to oncogenic activity in some cancers.

[0004] In normal cells, the RAS protein plays an important role in regulating cell growth, differentiation, and survival, functions as a molecular switch, and relays signals from cell surface receptors to intracellular pathways that control major cell processes. Genetic studies have demonstrated that complete deletion of the RAS gene is lethal in mouse models and leads to a lack of cell proliferation in vitro (Non-Patent Document 1, Non-Patent Document 2). Furthermore, conditional knockout of KRAS in adult bone marrow has been shown to induce significant hematopoietic defects, including splenomegaly, an expanded neutrophil compartment, and a reduction in B cell numbers (Non-Patent Document 3). Targeting mutant forms of RAS rather than wild-type RAS has emerged as a strategy for treating RAS mutant cancers because it specifically involves oncogenic signaling. Despite extensive drug discovery efforts against RAS over the past few decades, only two drugs targeting the KRAS G12C mutant form have been approved in the United States (sotorasib and adagrasib). However, both of these drugs target the "OFF" form of KRAS (KRAS , , , , (OFF) inhibitor) and are limited with respect to the depth and duration of response. The reasons for such limitations are multifactorial, but cancer cells appear to avoid inactivation state-selective inhibition by increasing the amount of drug-insensitive / GTP-bound KRASG12C.

[0005] Further efforts are needed to identify additional pharmaceuticals for cancers driven by the RASG12C mutation.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

[0007] A method for treating RAS protein-related disorders using compound A, which is a RAS inhibitor, or a pharmaceutically acceptable salt thereof, is provided herein. [ka]

[0008] In one embodiment, the present disclosure features a method for treating RAS protein-related disorders (e.g., cancer) in human subjects requiring treatment for RAS protein-related disorders (e.g., cancer). The method involves a total daily dose of 50 mg to 800 mg (e.g., 60 mg to 800 mg, 80 mg to 800 mg, 120 mg to 800 mg, 160 mg to 800 mg, 200 mg to 800 mg, 250 mg to 800 mg, 300 mg to 800 mg, 350 mg to 800 mg, 400 mg to 800 mg, 450 mg to 800 mg, 500 mg to 800 mg, 550 mg to 800 mg, 600 mg to 800 mg, 650 mg to 800 mg, 700 mg to 800 mg, 750 mg to 800 mg, 60 mg to 700 mg, 80 mg mg~700mg, 120mg~700mg, 160mg~700mg, 200mg~700mg, 250mg~700mg, 300mg~700mg, 350mg~700mg, 400mg~700mg, 450mg~700mg, 500mg~700m g, 550mg~700mg, 600mg~700mg, 650mg~700mg, 60mg~600mg, 80mg~600mg, 120mg~600mg, 160mg~600mg, 200mg~600mg, 250mg~600mg, 300mg~6 00mg, 350mg~600mg, 400mg~600mg, 450mg~600mg, 500mg~600mg, 550mg~600mg, 60mg~500mg, 80mg~500mg, 120mg~500mg, 160mg~500mg, 200m g~500mg, 220mg~500mg, 250mg~500mg, 300mg~500mg, 350mg~500mg, 400mg~500mg, 450mg~500mg, 60mg~400mg, 80mg~400mg, 120mg~400mg, 1 60mg~400mg, 200mg~400mg, 250mg~400mg, 300mg~400mg, 350mg~400mg, 50mg~300mg, 60mg~300mg, 80mg~300mg, 120mg~300mg, 160mg~300mg , 200mg~300mg, 250mg~300mg, 50mg~250mg, 60mg~250mg, 80mg~250mg, 120mg~250mg, 160mg~250mg, 50mg~200mg, 60mg~200mg, 80mg~200mg,This includes oral administration of compound A in total daily doses of 120mg-200mg, 160mg-200mg, 50mg-160mg, 60mg-160mg, 80mg-160mg, 120mg-160mg, 50mg-120mg, 60mg-120mg, 80mg-120mg, 50mg-80mg, 60mg-80mg, 70mg-80mg, 50mg-100mg, 60mg-100mg, or 80mg-100mg.

[0009] In some embodiments, this method is used for total daily doses of 50 mg to 800 mg (for example, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg) This includes administering compound A to a target in a total daily dose of mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg.

[0010] In some embodiments, the method includes administering a total daily dose of 200 mg to 600 mg, 225 mg to 575 mg, 250 mg to 550 mg, 275 mg to 525 mg, 300 mg to 500 mg, 325 mg to 475 mg, 350 mg to 450 mg, or 375 mg to 425 mg.

[0011] In some embodiments, the method includes administering 80 mg to 500 mg of compound A. In some embodiments, the method includes administering 90 mg to 500 mg of compound A. In some embodiments, the method includes administering 100 mg to 500 mg of compound A. In some embodiments, the method includes administering 120 mg to 500 mg of compound A. In some embodiments, the method includes administering 160 mg to 500 mg of compound A. In some embodiments, the method includes administering 200 mg to 500 mg of compound A. In some embodiments, the method includes administering 250 mg to 500 mg of compound A. In some embodiments, the method includes administering 300 mg to 500 mg of compound A. In some embodiments, the method includes administering 350 mg to 500 mg of compound A. In some embodiments, the method includes administering 400 mg to 500 mg of compound A. In some embodiments, the method includes administering 450 mg to 500 mg of compound A to the target.

[0012] In some embodiments, the method includes administering 80 mg to 400 mg of compound A. In some embodiments, the method includes administering 90 mg to 400 mg of compound A. In some embodiments, the method includes administering 100 mg to 400 mg of compound A. In some embodiments, the method includes administering 120 mg to 400 mg of compound A. In some embodiments, the method includes administering 160 mg to 400 mg of compound A. In some embodiments, the method includes administering 200 mg to 400 mg of compound A. In some embodiments, the method includes administering 220 mg to 400 mg of compound A. In some embodiments, the method includes administering 250 mg to 400 mg of compound A. In some embodiments, the method includes administering 300 mg to 400 mg of compound A. In some embodiments, the method includes administering 350 mg to 400 mg of compound A.

[0013] In some embodiments, the method includes administering 80 mg to 300 mg of compound A. In some embodiments, the method includes administering 90 mg to 300 mg of compound A. In some embodiments, the method includes administering 100 mg to 300 mg of compound A. In some embodiments, the method includes administering 120 mg to 300 mg of compound A. In some embodiments, the method includes administering 160 mg to 300 mg of compound A. In some embodiments, the method includes administering 200 mg to 300 mg of compound A. In some embodiments, the method includes administering 250 mg to 300 mg of compound A.

[0014] In some embodiments, the method includes administering 80 mg to 200 mg of compound A. In some embodiments, the method includes administering 90 mg to 200 mg of compound A. In some embodiments, the method includes administering 100 mg to 200 mg of compound A. In some embodiments, the method includes administering 120 mg to 200 mg of compound A. In some embodiments, the method includes administering 160 mg to 200 mg of compound A.

[0015] In some embodiments, compound A is administered to the subject daily. In some embodiments, compound A is administered to the subject once, twice, or more times daily. In some embodiments, compound A is administered to the subject once daily. In some embodiments, compound A is administered to the subject twice daily.

[0016] In some embodiments, the method includes administering 100 mg of compound A (i.e., a total daily dose of 200 mg) to the subject twice daily. In some embodiments, the method includes administering 200 mg of compound A (i.e., a total daily dose of 400 mg) to the subject twice daily. In some embodiments, the method includes administering 300 mg of compound A (i.e., a total daily dose of 600 mg) to the subject twice daily. In some embodiments, the method includes administering 400 mg of compound A (i.e., a total daily dose of 800 mg) to the subject twice daily.

[0017] In some embodiments, the RAS protein-related disorder is cancer. In some embodiments, the cancer includes a RAS mutation. In some embodiments, the RAS mutation is located at position 12. In some embodiments, the RAS mutation is G12C. In some embodiments, the cancer includes RAS amplification. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the Ras protein is KRAS. In some embodiments, the method further includes administering additional anticancer therapy. In some embodiments, the additional anticancer therapy is an EGFR inhibitor, a second RAS inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is a pan-RAS inhibitor. In some embodiments, the additional anticancer therapy is a RAS(ON) multiselective inhibitor. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. In some embodiments, the additional anticancer therapy comprises an SHP2 inhibitor and a PD-L1 inhibitor. In some embodiments, the additional therapy comprises a second RAS inhibitor and a PD-L1 inhibitor. In some embodiments, the second RAS inhibitor is a KRAS G12C It is an inhibitor. In some embodiments, the second RAS inhibitor is a RAS(ON)G12C selective inhibitor. In some embodiments, the second RAS inhibitor is a KRAS G12C It is an (OFF) inhibitor.

[0018] Any limitations discussed in relation to one embodiment of the present invention are specifically intended to be applicable to any other embodiment of the present invention. Furthermore, any compound or composition of the present invention can be used in any manner of the present invention, and any compound or composition of the present invention can be produced or utilized using any manner of the present invention. [Brief explanation of the drawing]

[0019] [Figure 1] The design for the Phase 1 study of compound A is shown. [Figure 2] This is a waterfall plot of the best overall response to compound A in KRASG12CNSCLC subjects previously treated with or naive to KRASG12C(OFF) inhibitors. (1) All treated patients who received the first dose of RMC-6291 at least 8 weeks prior to the date of data extraction. (2) Tumor response according to RECIST 1.1. (3) PR includes 5 confirmed and 3 unconfirmed PRs according to RECIST 1.1. Pru = unconfirmed PR according to RECIST 1.1, G12Ci = G12C inhibitor. [Figure 3] This study shows the best overall response to compound A in KRASG12C CRCs naive to KRASG12C(OFF) inhibitors. (1) All treated patients who received the first dose of RMC-6291 at least 8 weeks prior to the date of data extraction. (2) Tumor response according to RECIST 1.1. (3) PRs include 5 confirmed and 3 unconfirmed. (4) One patient had PD due to a new lesion, and measurement of the target lesion was not available. Pru = Unconfirmed PR according to RECIST 1.1. [Figure 4] The time-course profiles of mean plasma concentrations of compound A after daily (50 mg, 100 mg, and 200 mg) or twice-daily (200 mg) oral administration are shown. Outliers were excluded from the 50 mg cohort plot. [Modes for carrying out the invention]

[0020] Compound A is a RAS inhibitor, more specifically, a RAS(ON)G12C selective tricomplex inhibitor that is selective for the active GTP-binding state of canonical RAS isoforms having the G12C mutation. Compound A binds to cyclophyllin A, which is abundantly expressed in normal tissues and tumors, forming a two-component complex, which is RAS G12CIt covalently binds with (ON) to form a triplicate complex, blocking downstream RAS signaling (Schulze et.al., Science. 2023 Aug 18;381(6659):794-799).

[0021] definition In this application, unless otherwise clearly indicated by context, (i) the term “a” means “one or more,” (ii) the term “or” is used to mean “and / or” unless it is explicitly intended to refer only to the options or the options are not mutually exclusive, but this disclosure supports definitions referring only to the options and “and / or,” (iii) the terms “comprising” and “including” are understood to encompass the itemized components or steps, whether presented by themselves or together with one or more additional components or steps, and (iv) where a scope is indicated, it includes endpoints.

[0022] As used herein, the term “approximately” is used to indicate that a value includes the standard deviation of the error of the device or method used to determine the value. In certain embodiments, unless otherwise stated or evident from the content (for example, if such a number exceeds 100% of the possible values), the term “approximately” refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1% or less in either direction (above or below) of the stated value.

[0023] Unless otherwise indicated, where a range or amount is provided in this disclosure, it should be noted that each range endpoint or a specific amount includes + / - 5%. For example, the range of compound A from 50 mg to 800 mg is understood to include 50 mg (+ / - 5%) to 800 mg (+ / - 5%), for example, 47.5 mg to 840 mg of compound A.

[0024] As used herein, the term “administration” refers to the administration of a composition containing compound A to a subject or system. Administration also includes administering to a subject a prodrug derivative or analogue, or a pharmaceutically acceptable salt, which can form an equivalent amount of the active compound in the body of the subject. Administration to an animal subject (e.g., human) may be by any suitable route. For example, in some embodiments, administration may be bronchial (including bronchial infusion), cheek, enteral, intradermal, intra-arterial, intradermal, gastric, intramedullary, intramuscular, transnasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, intratracheal (including intratracheal infusion), transdermal, vaginal, or intravitreous. In some embodiments, the composition containing compound A is administered orally.

[0025] The term "combination therapy" refers to a treatment method that involves administering to a subject, as part of a treatment regimen, at least two active therapeutic agents as one or more pharmaceutical compositions. For example, combination therapy may include the administration of a single pharmaceutical composition comprising at least two therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. Combination therapy may include the administration of two or more pharmaceutical compositions, each comprising one or more therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. The two or more agents may optionally be administered simultaneously (as a single or separate composition) or sequentially (as separate compositions). The therapeutic agents may be administered in an effective dose. The therapeutic agents may be administered in a therapeutically effective dose. In some embodiments, the effective dose of one or more therapeutic agents may be less when used in combination therapy than the therapeutic dose of the same therapeutic agent when used as a monotherapy, for example, due to the added or synergistic effect of combining two or more therapeutic agents.

[0026] As used herein, the term “dosage form” refers to a physically distinct unit of a compound (e.g., compound A) for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, such an amount is a unit dose (or its entire fraction) appropriate for administration according to an administration regimen (i.e., using a therapeutic administration regimen) that has been determined to correlate with a desired or beneficial outcome when administered to a suitable population. Those skilled in the art will understand that the total amount of a therapeutic composition or compound administered to a particular subject may be determined by one or more attending physicians and may involve administration in multiple dosage forms.

[0027] As used herein, the term “dosage regimen” refers to a set of unit doses (usually two or more) administered individually to a subject, typically separated by a period of time. In some embodiments, a given therapeutic compound (e.g., compound A) has a recommended dosage regimen, which may consist of one or more doses. In some embodiments, the dosage regimen comprises multiple doses, each separated from the others by periods of equal length, and in some embodiments, the dosage regimen comprises multiple doses and at least two different periods separating the individual doses. In some embodiments, all doses within the dosage regimen are the same unit dose. In some embodiments, the different doses within the dosage regimen are different amounts. In some embodiments, the dosage regimen comprises a first dose at a first dose, followed by one or more further doses at a second dose different from the first dose. In some embodiments, the dosage regimen comprises a first dose at a first dose, followed by one or more further doses at a second dose that is the same as the first dose. In some embodiments, the administration regimen correlates with a desired or beneficial outcome when administered across the relevant population (i.e., it is a therapeutic administration regimen).

[0028] The term “disability” is used in this disclosure to mean, and is interchangeable with, the terms “disease,” “condition,” or “illness,” unless otherwise indicated.

[0029] The terms “inhibit,” “block,” and “suppress” are used interchangeably and refer to any statistically significant reduction in biological activity, including complete blockade of activity. As used herein, the term “inhibitor” refers to a compound that prevents a biomolecule (e.g., protein, nucleic acid) from completing or initiating a reaction. Inhibitors can inhibit a reaction by competitive, non-competitive, or non-competitive means, for example. With respect to its binding mechanism, an inhibitor may be an irreversible or reversible inhibitor. Exemplary inhibitors include, but are not limited to, nucleic acids, DNA, RNA, shRNA, siRNA, proteins, protein mimics, peptides, peptide mimics, antibodies, small molecules, chemicals, enzymes, receptors, or analogs that mimic the binding sites of other proteins. In some embodiments, the inhibitor is a small molecule, e.g., a low molecular weight organic compound, e.g., an organic compound having a molecular weight (MW) of less than 1200 Daltons (Da). In some embodiments, the MW is less than 1100 Da. In some embodiments, the MW is less than 1000 Da. In some embodiments, the MW is less than 900 Da. In some embodiments, the MW range of the small molecule is 800 Da to 1200 Da. Small molecule inhibitors include cyclic and acyclic compounds. Small molecule inhibitors include their natural products, derivatives, and analogs. Small molecule inhibitors may include, for example, covalent crosslinking groups capable of forming covalent crosslinks with the amino acid side chains of a target protein.

[0030] As used herein, “patient” or “subject” are used interchangeably and refer to a mammal for which diagnosis, prognosis, or treatment is desired. Mammal subjects include, but are not limited to, humans, livestock, farm animals, sporting animals, and zoo animals, including, for example, humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, and cattle. In certain embodiments, the subject is diagnosed with cancer. In certain embodiments, the subject is a human being who has a tumor (e.g., cancer) and is diagnosed with a need for treatment of the tumor (e.g., cancer).

[0031] As used herein, the term “pharmaceutical composition” means a compound such as Compound A disclosed herein, or a pharmaceutically acceptable salt thereof, formulated with pharmaceutically acceptable excipients.

[0032] As used herein, “pharmaceutically acceptable excipients” refers to any inert component (e.g., a vehicle capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in the subject matter. Typical excipients include, for example, antifouling agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavoring agents, fragrances, flow enhancers, lubricants, preservatives, printing inks, adsorbents, suspending agents or dispersants, sweeteners, or hydration water. Examples of excipients include, but are not limited to, optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolic acid, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are familiar with a wide variety of agents and materials useful as excipients.See, for example, Ansel, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0033] As used herein, the term “pharmaceutically acceptable salt” refers to salts of the compounds described herein that are suitable for use in contact with human and other animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., within the normal range of reasonable medical judgment, and that are balanced by a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:119, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PHStahl and CGWermuth), Wiley VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting free base groups with suitable organic acids.

[0034] The terms "RAS inhibitor" and "inhibitor of RAS" are used interchangeably and refer to any inhibitor that targets the RAS protein, i.e., selectively binds to or selectively inhibits the RAS protein.

[0035] As used herein, the terms “RAS(ON) multiselective inhibitor,” “RASMULTI inhibitor,” “RASMULTI(ON) inhibitor,” and “RAS(MULTI) inhibitor” refer to RAS inhibitors of at least three RAS isoforms, including the wild type and / or variants having a missense mutation at one of the following positions: 12, 13, 59, 61, or 146. In some embodiments, a RAS(ON) multiselective inhibitor refers to a RAS inhibitor of at least three RAS variants having a missense mutation at one of the following positions: 12, 13, and 61.

[0036] As used herein, the term “RAS(ON) variant-selective inhibitor” refers to an RAS inhibitor that is selective for RAS(ON) variants having a missense mutation at one of the following positions: 12, 13, or 61. Non-exclusive examples of RAS(ON) variant-selective inhibitors include RAS(ON)G12C selective inhibitors, RAS(ON)G12D selective inhibitors, RAS(ON)Q61H selective inhibitors, RAS(ON)G12V selective inhibitors, and RAS(ON)G13D selective inhibitors.

[0037] As used herein, the term “RAS(ON) inhibitor” refers to an inhibitor that targets, i.e., selectively binds to or selectively inhibits the GTP-bound active state of RAS (e.g., more selectively than GDP-bound inactive RAS). Inhibition of the GTP-bound active state of RAS includes, for example, the inhibition of oncogenic signaling from the GTP-bound active state of RAS. In some embodiments, a RAS(ON) inhibitor is an inhibitor that selectively binds to and inhibits the GTP-bound active state of RAS. In certain embodiments, a RAS(ON) inhibitor may also bind to or inhibit the GDP-bound inactive state of RAS (e.g., with lower affinity or inhibition constant than GTP-bound active RAS). In certain embodiments, RAS(ON) inhibitors useful to this disclosure may form a high-affinity triplicate or conjugate between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: a target protein of interest (e.g., RAS) and a cytosolic chaperone (presenter protein) that is widely expressed intracellularly (e.g., cyclophyllin A). More specifically, in some embodiments, the RAS inhibitors described herein induce a novel binding pocket in RAS by driving the formation of a high-affinity triplicate or conjugate between the RAS protein and the widely expressed cytosolic chaperone cyclophyllin A (CYPA).

[0038] As used herein, the term “RAS(OFF) inhibitor” refers to an inhibitor that targets, i.e., selectively binds to or selectively inhibits the GDP-bound, inactive RAS (for example, more selectively than the GTP-bound, active RAS).

[0039] The terms “RAS pathway” and “RAS / MAPK pathway” are used interchangeably herein and refer to a signal transduction cascade downstream of various cell surface growth factor receptors, where the activation of RAS (and its diverse isoforms and allotypes) is a central event driving various cellular effector events that determine cell proliferation, activation, differentiation, mobility, and other functional properties. SHP2 transmits a positive signal from the growth factor receptor to the RAS activation / deactivation cycle, which is regulated by guanine nucleotide exchange factors (GEFs such as SOS1) that load GTP into RAS to produce functionally active, GTP-bound RAS, and GTP-accelerating proteins (GAPs such as NF1) that facilitate the termination of the signal by converting GTP to GDP. The GTP-bound RAS produced by this cycle transmits essential positive signals to a series of serine / threonine kinases, including RAFs and MAP kinases, from which further signals extend to various cellular effector functions.

[0040] A “therapeutic agent” is any substance, such as a compound or composition, that is capable of treating a disease or disorder. In some embodiments, therapeutic agents useful in combination with the present disclosure include RAS inhibitors and cancer chemotherapy agents. Many such therapeutic agents are known in the art and are disclosed herein.

[0041] The term “therapeutic dose” means an amount sufficient to treat a disease, disorder, or condition when administered to a population suffering from or suspected of having a disease, disorder, or condition, according to a therapeutic administration regimen. In some embodiments, the therapeutic dose is an amount that reduces the onset or severity of one or more symptoms of the disease, disorder, or condition, or delays the onset of one or more symptoms of the disease, disorder, or condition. Those skilled in the art will understand that the term “therapeutic dose” does not actually require that successful treatment be achieved in a particular individual. Rather, the therapeutic dose can be an amount that, when administered to subjects requiring such treatment, produces a particular desired pharmacological response in a significant number of subjects. It is specifically understood that a particular subject may actually be “refractory” to the “therapeutic dose.” In some embodiments, the reference to the therapeutic dose may refer to an amount measured in one or more specific tissues (e.g., tissues affected by the disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, the therapeutically effective dose may be formulated or administered as a single dose. In some embodiments, the therapeutically effective dose may be formulated or administered in multiple doses, for example, as part of an administration regimen.

[0042] The term “treatment” (also “to treat” or “to treat”), in its broadest sense, refers to any administration of a substance (e.g., compound A) that partially or completely alleviates, improves, reduces, inhibits, delays the onset, reduces the severity, or decreases the incidence of one or more symptoms, characteristics, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment may be administered to subjects who show no signs of the related disease, disorder, or condition, or to subjects who show only initial signs of the disease, disorder, or condition. Alternatively or additionally, in some embodiments, treatment may be administered to subjects who show one or more established signs of the related disease, disorder, or condition. In some embodiments, treatment may be administered to subjects diagnosed with the related disease, disorder, or condition. In some embodiments, treatment may be administered to subjects known to have one or more susceptibility factors that are statistically correlated with an increased risk of progression of the related disease, disorder, or condition. In any treatment method herein, a patient or subject may require such treatment.

[0043] Treatment method In general, this disclosure features a method for treating RAS protein-related disorders (e.g., cancer) in human subjects requiring treatment for RAS protein-related disorders (e.g., cancer), the method comprising administering 50 mg to 800 mg of compound A daily (e.g., orally): [ka]

[0044] Compound A can exist as conformational stereoisomers such as atropisomers. Pharmaceutically acceptable salts of Compound A are also contemplated as solvates, hydrates, and polymorphs. See, for example, WO2021 / 091982 and PCT / US2024 / 024246, which are hereby incorporated by reference in their entirety. Compound A can be prepared as described in WO2021 / 091982 and WO2022 / ******64, each of which is hereby incorporated by reference in its entirety.

[0045] Compound A can exist as a pharmaceutically acceptable isotopically labeled version, where one or more atoms are replaced by an atom having the same atomic number but a different atomic mass or mass number than the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into Compound A include, respectively, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, and 18 O isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine. These radiolabeled compounds can be useful, for example, in helping to determine or measure the efficacy of Compound A by characterizing the site or mode of action. Certain isotopically labeled versions of Compound A, such as those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose in view of their ease of incorporation and available means of detection.

[0046] Substitution with a heavier isotope such as deuterium, i.e., 2 H, can result in certain therapeutic advantages from increased metabolic stability, e.g., increased in vivo half-life, or reduced required dosage.11 C, 15 O, and 13 Substitution with positron-emitting isotopes such as 1N may be useful in positron emission topography (PET) studies.

[0047] Further methods are provided for treating cancer in subjects requiring cancer treatment, the methods comprising administering a therapeutically effective amount of compound A to the subject. The cancer may be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or squamous cell lung cancer. In some embodiments, the cancer includes a RAS mutation such as KRAS G12C. In some embodiments, the cancer including the KRAS G12C mutation may further include additional RAS mutations. Other RAS mutations are described herein.

[0048] A method for treating RAS protein-related disorders in subjects requiring treatment for RAS protein-related disorders is further provided, the method comprising administering a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof to the subject.

[0049] In some embodiments of any of the methods described herein, the method involves a total daily dose of compound A (e.g., 60mg-800mg, 80mg-800mg, 120mg-800mg, 160mg-800mg, 200mg-800mg, 250mg-800mg, 300mg-800mg, 350mg-800mg, 400mg-800mg, 450mg-800mg, 500mg-800mg, 550mg-800mg, 600mg-800mg, 650mg-800mg, 700mg-800mg, 750mg-800mg) g, 60mg~700mg, 80mg~700mg, 120mg~700mg, 160mg~700mg, 200mg~700mg, 250mg~700mg, 300mg~700mg, 350mg~700mg, 400mg~700mg, 450mg~700mg, 500mg ~700mg, 550mg~700mg, 600mg~700mg, 650mg~700mg, 60mg~600mg, 80mg~600mg, 120mg~600mg, 160mg~600mg, 200mg~600mg, 250mg~600mg, 300mg~600mg, 350mg~600mg, 400mg~600mg, 450mg~600mg, 500mg~600mg, 550mg~600mg, 60mg~500mg, 80mg~500mg, 120mg~500mg, 160mg~500mg, 200mg~500mg, 220mg~5 00mg, 250mg~500mg, 300mg~500mg, 350mg~500mg, 400mg~500mg, 450mg~500mg, 60mg~400mg, 80mg~400mg, 120mg~400mg, 160mg~400mg, 200mg~400mg, 25 0mg~400mg, 300mg~400mg, 350mg~400mg, 50mg~300mg, 60mg~300mg, 80mg~300mg, 120mg~300mg, 160mg~300mg, 200mg~300mg, 250mg~300mg, 50mg~250mg , 60mg~250mg, 80mg~250mg, 120mg~250mg, 160mg~250mg, 50mg~200mg, 60mg~200mg, 80mg~200mg, 120mg~200mg, 160mg~200mg, 50mg~160mg, 60mg~160mg,This includes administration of a total daily dose of 80mg-160mg, 120mg-160mg, 50mg-120mg, 60mg-120mg, 80mg-120mg, 50mg-80mg, 60mg-80mg, 70mg-80mg, 50mg-100mg, 60mg-100mg, or 80mg-100mg to subjects requiring it. In each of the prior embodiments, the total daily dose may be administered once or twice daily.

[0050] In some applications, this method is applicable to doses of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, This involves administering a total daily dose of compound A of 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg to a subject requiring it. In each of the prior embodiments, the total daily dose may be administered once or twice daily.

[0051] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 300 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 400 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 450 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 500 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 550 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 600 mg to 800 mg to a subject requiring it.In some embodiments, the method includes administering a total daily dose of compound A of 650 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 700 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 750 mg to 800 mg to a subject requiring it.

[0052] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 300 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 400 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 450 mg to 800 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 500 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 550 mg to 700 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 600 mg to 800 mg to a subject requiring it.In some embodiments, the method involves administering a total daily dose of compound A of 650 mg to 700 mg to a subject requiring it.

[0053] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 300 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 400 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 450 mg to 600 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 500 mg to 600 mg to a subject requiring it. In some embodiments, the method involves administering a total daily dose of compound A of 550 mg to 600 mg to a subject requiring it.

[0054] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 300 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 400 mg to 500 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 450 mg to 500 mg to a subject requiring it.

[0055] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 400 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 400 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 400 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 400 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 400 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 400 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 400 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 400 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 400 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 300 mg to 400 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to 400 mg to a subject requiring it.

[0056] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 300 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 300 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 300 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 300 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 300 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 300 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 300 mg to a subject requiring it. In some embodiments, the method involves administering a total daily dose of compound A of 200 mg to 300 mg to a subject requiring it. In some embodiments, the method involves administering a total daily dose of compound A of 250 mg to 300 mg to a subject requiring it.

[0057] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 200 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 200 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 200 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 200 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 200 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 200 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 200 mg to a subject requiring it.

[0058] In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 225 mg to 575 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 550 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 275 mg to 525 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 300 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 325 mg to 475 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to 450 mg to a subject in need. In some embodiments, the method involves administering a total daily dose of compound A of 375 mg to 425 mg to a subject requiring it.

[0059] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 160 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 160 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 160 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 160 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 160 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 160 mg to a subject requiring it.

[0060] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 120 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 120 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 120 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 120 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 120 mg to a subject requiring it.

[0061] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 100 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 100 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 100 mg to a subject requiring it. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 100 mg to a subject requiring it.

[0062] In some embodiments, the method includes administering a total daily dose of 50 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 60 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 70 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 80 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 100 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 120 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 160 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 200 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 250 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 300 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 350 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 400 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 450 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 500 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 550 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 600 mg of compound A to a subject in need. In some embodiments, the method includes administering a total daily dose of 650 mg of compound A to a subject in need.In some embodiments, the method includes administering a total daily dose of 700 mg of compound A to a subject requiring it. In some embodiments, the method includes administering a total daily dose of 750 mg of compound A to a subject requiring it. In some embodiments, the method includes administering a total daily dose of 800 mg of compound A to a subject requiring it.

[0063] In various embodiments, compound A is administered daily. In some embodiments, compound A is administered once, twice, or more times daily. In some embodiments, compound A is administered twice daily. In various embodiments, compound A is administered in divided daily doses, such as two, three, four, five, or six times a day.

[0064] In some embodiments of the methods disclosed herein, subjects are administered compound A orally once daily (QD) at the doses disclosed herein.

[0065] In some embodiments of the methods disclosed herein, subjects are administered compound A orally twice daily (BID) at the doses disclosed herein.

[0066] In some embodiments of the methods disclosed herein, the subject is administered 175 mg to 325 mg of compound A by biopsy (BID). In some embodiments, the method includes administering 200 mg to 300 mg of compound A by biopsy to a subject in need. In some embodiments, the method includes administering 225 mg to 275 mg of compound A by biopsy to a subject in need. In some embodiments, the method includes administering 200 mg of compound A by biopsy to a subject in need. In some embodiments, the method includes administering 300 mg of compound A by biopsy to a subject in need. In some embodiments, the method includes administering 400 mg of compound A by biopsy to a subject in need.

[0067] In some embodiments, the methods or uses described herein further include administering additional anticancer therapies. In some embodiments, the additional anticancer therapy is a HER2 inhibitor, an EGFR inhibitor, a second RAS inhibitor (e.g., a pan-KRAS inhibitor or a RAS(ON) multiselective inhibitor), a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. Other combination therapies are described herein.

[0068] In various embodiments, compound A is administered once, two, three, four, five, six, or seven times per week. In various embodiments, compound A is administered seven days a week. In various embodiments, compound A is administered six days a week. For example, compound A is administered on days 1, 2, 3, 4, 5, and 6 of each seven-day period. In various embodiments, compound A is administered five days a week. For example, compound A is administered on days 1, 2, 3, 4, and 5 of each seven-day period. In various embodiments, compound A is administered four days a week. For example, compound A is administered on days 1, 2, 3, and 4 of each seven-day period. In various embodiments, compound A is administered three days a week. For example, compound A is administered on days 1, 2, and 3 of each seven-day period. In various embodiments, compound A is administered two days a week. For example, compound A is administered on day 1 and day 2 of each 7-day period.

[0069] In various embodiments, the subject is administered compound A for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, for example, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, 24 months, or longer. In various embodiments, the subject is administered compound A for at least 1 month. In various embodiments, the subject is administered compound A for at least 3 months. In various embodiments, the subject is administered compound A for at least 6 months. In various embodiments, the subject is administered compound A for at least 8 months. In various embodiments, the subject is administered compound A for at least 10 months. In various embodiments, the subject is administered compound A for at least 12 months.

[0070] In some embodiments, compound A is administered in a treatment cycle. In some embodiments, the treatment cycle is 7 days, 14 days, 21 days, 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year. In various embodiments, the subject receives 1, 2, 3, 4, or more treatment cycles. In some embodiments, the subject receives at least 3, at least 5, at least 8, at least 10, at least 15, at least 20, at least 25, or more treatment cycles.

[0071] The response rate or results of subjects administered compound A by the method disclosed herein can be measured in various ways after the subjects have ingested compound A for a suitable period of time, as is known to those skilled in the art.

[0072] The subjects are those who can respond to therapy as measured by at least stable disease (SD), as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009). RECIST v1.1 is discussed in detail in the following examples. At least stable disease is defined as a stable disease, a disease that has shown a partial response (PR), or a disease that has shown a complete response (CR) (i.e., "at least SD" = SD + PR + CR, often referred to as disease control). In various embodiments, stable disease does not have either sufficient contraction to qualify for a partial response (PR) or sufficient increase to qualify for progressive disease (PD). In various embodiments, the patient shows at least a partial response (i.e., "at least PR" = PR + CR, often referred to as objective response).

[0073] The response can be measured by one or more of the following: reduction in tumor size, suppression or reduction of tumor growth, reduction in target or tumor lesions, delay in time to progression, no new tumors or lesions, reduced neotumor formation, increased survival or progression-free survival (PFS), and no metastasis. In various embodiments, disease progression in a patient can be assessed by evaluating the patient using computed tomography (CT) scans, positron emission tomography (PET) scans, magnetic resonance imaging (MRI) scans, X-rays, ultrasound, or a combination thereof, by measuring tumor size, tumor lesions, or the formation of new tumors or lesions.

[0074] To determine the effectiveness of one or more treatments for a tumor in a person affected by cancer, several criteria and definitions published in the literature can be used. Based on these criteria, a tumor is defined as “responsive,” “stable,” or “progressive” depending on whether it improves, remains the same, or worsens during treatment, respectively. The amount of tumor in an individual is the “tumor load,” which can be measured as the number, volume, and / or weight of tumors.

[0075] Examples of commonly used criteria published in the literature include the Criteria for Evaluation of Solid Tumors (RECIST), the Modified Criteria for Evaluation of Solid Tumors (mRECIST), the PET Criteria for Evaluation of Solid Tumors (PERCIST), the Choi Criteria, the Lugano Criteria, the European Association for the Study of the Liver (EASL) Criteria, the Criteria for Evaluation of Treatment Response to Hepatocellular Carcinoma (RECICL), and the WHO Criteria for Tumor Response.

[0076] As used herein, “progression-free survival” or “PFS” is the time from treatment to the first confirmed disease progression according to the RECIST 1.1 criteria. In various embodiments, patients exhibit a PFS of at least one month. In various embodiments, patients exhibit a PFS of at least three months. In some embodiments, patients exhibit a PFS of at least six months.

[0077] "RECIST" is an acronym for "Response Evaluation Criteria in Solid Tumors," a set of published rules that define when a cancer patient improves ("response"), maintains the same condition ("stable"), or worsens ("progression") during treatment. The responses defined by the RECIST criteria are published, for example, in the Journal of the National Cancer Institute, Vol. 92, No. 3, Feb. 2, 2000, and the RECIST criteria may include other similar published definitions and sets of rules. Those skilled in the art will understand the definitions that conform to the RECIST criteria, such as "partial response (PR)," "complete response (CR)," "stable disease (SD)," and "progressive disease (PD)," as used herein.

[0078] As used herein, “survival” refers to a living subject, including overall survival and progression-free survival.

[0079] As used herein, “tumor reduction” means reducing the size, volume, or weight of a tumor, reducing the number of metastases, reducing the size or weight of metastases, or a combination thereof. In certain embodiments, metastases are cutaneous or subcutaneous. Thus, in certain embodiments, administration of an immune checkpoint inhibitor reduces the size or volume of a tumor by, for example, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% compared to a control drug in a subject of the same genotype. In certain embodiments, administration of compound A or a combination therapy containing it reduces tumor weight by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% compared to a control drug in a subject of the same genotype. In certain embodiments, administration of compound A or a combination therapy containing it reduces metastasis size or volume by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% compared to a control drug in a subject of the same genotype. In certain embodiments, administration of RAS(ON) inhibitor therapy or combination therapy including the same reduces the number of metastases by, for example, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% compared to a control drug in a subject of the same genotype. In certain embodiments, a combination of these effects is achieved.

[0080] In some embodiments, a biological sample obtained from a subject is used to determine the response to treatment with compound A. As used herein, the term “biological sample” refers to any sample obtained from a subject. A biological sample may be obtained from a subject at one or more time points before or after diagnosis, before or after treatment or therapy, at one or more time points in the absence of treatment or therapy, or it may be collected from a healthy subject. A biological sample may be a tissue sample or a fluid sample. In certain embodiments, a biological sample includes a tissue sample, a biopsy sample, a tumor aspirate, a bone marrow aspirate, or a blood sample (or a fraction thereof, such as blood or serum). In certain embodiments, a biological sample includes tumor cells or cancer cells, e.g., a fluid sample, e.g., circulating tumor cells present in blood or a fraction thereof. In certain embodiments, a biological sample includes a fluid sample, e.g., cell-free nucleic acids present in blood or a fraction thereof. In one embodiment, a biological sample includes a cell lysate (or lysate fraction) or cell extract, or a solution containing one or more molecules (e.g., polypeptides or nucleic acids) derived from cells or cell material. A cell lysate may include proteins, nuclei, and / or mitochondrial fractions. In certain embodiments, the cell lysate includes a cytoplasmic fraction. In certain embodiments, the cell lysate includes a nuclear / mitochondrial fraction and a cytoplasmic fraction.

[0081] The source of the biological sample may be solid tissue from fresh, frozen, and / or preserved organs, tissue samples, biopsies, or aspirates; blood or any blood component; body fluids such as cerebrospinal fluid, amniotic fluid, ascites, or interstitial fluid; or cells from any point in time during the subject's pregnancy or development. The biological sample may contain compounds that do not naturally mix with natural tissues, such as preservatives, anticoagulants, buffers, fixatives, nutrients, and antibiotics. The biological sample may be preserved as a frozen sample or as a formaldehyde-fixed paraffin-embedded (FFPE) tissue preparation. For example, the sample may be embedded in a matrix, such as an FFPE block or a frozen sample. However, other types of tissues and samples are suitable for use herein. In one embodiment, other types of tissues and samples may be fresh frozen tissue, washing solutions, or cell pellets. The biological sample may be a tumor sample containing nucleic acid molecules derived from a tumor or cancer. The biological sample, being a tumor sample, may be DNA, such as genomic DNA, or cDNA derived from RNA. In one embodiment, the tumor nucleic acid sample is purified or isolated (e.g., taken from its natural state). In one embodiment, the sample is tissue (e.g., tumor biopsy), CTC, or cell-free nucleic acid.

[0082] In certain embodiments, tumor samples are isolated from human subjects. In certain embodiments, analysis is performed on tumor biopsies embedded in paraffin wax. In one embodiment, the sample may be a fresh, frozen tissue sample. In certain embodiments, the sample may be a body fluid obtained from a subject. The body fluid may be blood or a fraction thereof (specifically, serum, plasma), urine, saliva, sputum, or cerebrospinal fluid (CSF). The sample may contain both cellular and extracellular sources of nucleic acids. The extracellular source may be cell-free nucleic acids and / or exosomes. Methods described herein, including RT-PCR methods, are highly sensitive, accurate, and have multi-analyte capabilities for use with paraffin-embedded samples. See, for example, Cronin et al., Am. J Pathol. 164(1):35-42 (2004).

[0083] Additional means for evaluating the response are described in detail in the following examples and can generally be applied to the methods disclosed herein.

[0084] In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering the subject an amount of compound A as described herein. Accordingly, one embodiment of the Disclosure provides a method for treating a subject in need of treatment by administering a pharmaceutical composition containing an amount of compound A as described herein and a pharmaceutically acceptable excipient, as well as a method for using compound A to prepare such a composition.

[0085] In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including: oral administration, e.g., oral medication (aqueous or nonaqueous solution or suspension), tablets, e.g., targeted for buccal, sublingual, and systemic absorption, bolus, powder, granules, paste for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., sterile solution or suspension, or sustained-release formulation; topical application, e.g., as a cream, ointment, or controlled-release patch or spray applied to the skin, lungs, or oral cavity; e.g., as a pessary, cream, or foam for vaginal or rectal administration; sublingual; ocular; transdermal; or transnasal, pulmonary, and other mucosal surfaces.

[0086] Compound A can be formulated as a pharmaceutical composition for use as a treatment for a target. Depending on the target being treated, the method of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy, compound A is formulated in a manner that matches these parameters. A summary of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21 st This information can be found in Edition, Lippincott Williams & Wilkins, (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988–1999, Marcel Dekker, New York, each of which is incorporated herein by reference in its entirety.

[0087] Each composition can be prepared according to conventional mixing, granulation, or coating methods, and the pharmaceutical composition may contain compound A in amounts of about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% by weight or volume. In some embodiments, compound A may be present in total in an amount of 1% to 95% of the total weight of the composition, such as the pharmaceutical composition.

[0088] The composition can be provided in dosage forms suitable for intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, transnasal, intravaginal, intrabladderal, intraurethral, ​​intrathecal, epidural, transaural, or intraocular administration, or for injection, inhalation, or direct contact with the nasal, genitourinary, reproductive, or oral mucosa. Accordingly, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels containing hydrogels, pastes, ointments, creams, plasters, oral medications, infiltration delivery devices, suppositories, enemas, injections, implants, sprays, preparations suitable for iontophoresis delivery, or aerosols. The composition can be formulated according to conventional pharmaceutical regulations.

[0089] Formulations can be prepared in a manner suitable for systemic administration or local or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection), or they can be prepared for transdermal, transmucosal, or oral administration. Formulations generally include diluents and, in some cases, adjuvants, buffers, preservatives, etc. The compound, or a pharmaceutically acceptable salt thereof, can also be administered in a liposome composition or as a microemulsion.

[0090] For injection, the formulation may be prepared in conventional forms, such as a solution or suspension, or as a solid suitable for solution or suspension in liquid before injection, or as an emulsion. Suitable excipients include, for example, water, physiological saline, dextrose, and glycerol. Such compositions may also contain certain amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate and sorbitan monolaurate.

[0091] Various sustained-release systems for drugs have also been devised. See, for example, U.S. Patent No. 5,624,677.

[0092] Systemic administration may also involve relatively non-invasive methods, such as suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or their pharmaceutically acceptable salts. Preferred forms include syrups, capsules, and tablets, as understood in the art. In one embodiment, a therapeutically effective amount of compound A is administered orally in the form of a tablet or a group of tablets.

[0093] Compound A as described herein can be formulated in various ways known in the art. For example, the first and second agents of combination therapy can be formulated together or separately. Other modalities of combination therapy are described herein.

[0094] Individually or separately formulated preparations can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing two pills, pills and powder, suppositories and liquids in vials, or two topical creams. Kits may include optional components that facilitate the administration of a unit dose to a subject, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, or inhalers. Additionally, unit dose kits may include instructions for use for the preparation or administration of the composition. Kits may be manufactured as single-use unit doses for a particular subject (where the efficacy of individual compounds or their pharmaceutically acceptable salts changes at a constant concentration or as treatment progresses), as multiple-use doses for a specific subject, or as multi-use doses suitable for administration to multiple subjects ("bulk packaging"). The components of a kit may be assembled into cartons, blister packs, bottles, tubes, etc.

[0095] Preparations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic, pharmaceutically acceptable excipients. These excipients may include, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starch containing potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulators and disintegrants (e.g., cellulose derivatives containing microcrystalline cellulose, starch containing potato starch, croscarmellose sodium, alginate, or arginine); binders (e.g., sucrose, glucose, sorbitol, acacia, arginine, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, aluminum magnesium silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); as well as smoothers, lubricants, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may include colorants, flavoring agents, plasticizers, wetting agents, and buffering agents.

[0096] Two or more compounds can be mixed or dispensed in a tablet, capsule, or other vehicle. In one example, the first compound is contained inside the tablet and the second compound is on the outside, such that a substantial portion of the second compound is released before the first compound is released.

[0097] Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules in which compound A is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which compound A is mixed with a watery or oily medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets may be prepared using the above-described components in conventional methods, for example, using a mixer, fluidized bed apparatus, or spray dryer, along with tablets and capsules.

[0098] Dissolution or diffusion-controlled release can be achieved by appropriate coatings for tablet, capsule, pellet, or granule formation of the compound, or by incorporating compound A into an appropriate matrix. A controlled-release coating may contain one or more of the above-mentioned coating materials, or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate / butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-(optionally substituted) hydroxyl methacrylate, methacrylate hydrogel, 1,3-butylene glycol, ethylene glycol methacrylate, or polyethylene glycol. In controlled-release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, Carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0099] Liquid forms in which compound A, or a composition thereof, can be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0100] In some embodiments, the pharmaceutical composition may further comprise additional compounds having antiproliferative activity. Depending on the method of administration, the compounds, or pharmaceutically acceptable salts thereof, are formulated into a suitable composition that allows for easy delivery. Each compound, or pharmaceutically acceptable salt thereof, of the combination therapy can be formulated in various ways known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Preferably, the first and second agents are formulated together for simultaneous or nearly simultaneous administration.

[0101] Compound A and its pharmaceutical compositions can be formulated and used in combination therapy; that is, compound A and its pharmaceutical compositions can be formulated or administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutic agents or procedures) using a combination regimen will take into account the suitability of the desired therapeutic agent or procedure and the desired therapeutic effect to be achieved. Furthermore, the therapies used may achieve the desired effect for the same disorder or different effects (e.g., control of any adverse effects).

[0102] In combination therapy, each drug may be administered independently, as described herein, 1 to 4 times daily for 1 to 1 year, and may even be administered for the lifetime of the patient. Chronic long-term administration may be indicated.

[0103] In some embodiments, the present disclosure provides a method for treating a disease or disorder characterized by abnormal RAS activity due to a RAS G12C mutation. In some embodiments, the disease or disorder is cancer.

[0104] Accordingly, this disclosure provides a method for treating cancer in subjects requiring treatment for cancer, the method comprising administering a certain amount of Compound A disclosed herein, or a pharmaceutical composition containing the same, to a subject. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small intestine cancer, ampulla cancer, germ cell carcinoma, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophageal cancer, GI neuroendocrine cancer, ovarian cancer, sex cord-stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal cancer, endometrial cancer, or melanoma. Furthermore, a method for treating RAS protein-related disorders in subjects requiring treatment for RAS protein-related disorders is also provided, the method comprising administering a therapeutically effective amount of the Compound of the Invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such Compound or salt, to a subject.

[0105] As used herein, the terms “cancer” or “tumor” refer to the presence of cells that have characteristics typical of cancer-causing cells, including uncontrolled growth, immortality, metastatic potential, rapid growth and proliferation rates, and certain characteristic morphological features. While cancer cells are often in the form of tumors, such cells may exist isolated within animals or may be non-tumorous, such as leukemia cells. Cancer includes, but is not limited to, B-cell malignancies such as multiple myeloma, heavy-chain diseases such as alpha-chain diseases, gamma-chain diseases, and μ-chain diseases, benign monoclonal gammaglobulinemia, and immunocellular amyloidosis, skin cancer, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, pancreatic cancer, stomach cancer, ovarian cancer, bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical cancer, uterine or endometrial cancer, oral or pharyngeal cancer, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small intestine or appendiceal cancer, salivary gland cancer, thyroid cancer, adrenal cancer, osteosarcoma, chondrosarcoma, and hematological cancers. Other non-limiting examples of cancer types applicable to the methods contained herein include human sarcomas and carcinomas, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphangiosarcoma, synoviomas, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic lung cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, liver cancer, choriocarcinoma, seminoma, embryonic carcinoma, Wilms' tumor, cervical cancer, bone cancer, and brain tumors. These include ulcers, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal glandoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemia, such as acute lymphoblastic leukemia and acute myeloid leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myeloid (granulocytic) leukemia and chronic lymphocytic leukemia); as well as polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenström macroglobulinemia, and heavy chain diseases.In some embodiments, the cancer is an epithelial cancer, including but not limited to bladder cancer, breast cancer, cervical cancer, colon cancer, gynecological cancer, kidney cancer, laryngeal cancer, lung cancer, oral cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, or skin cancer. In other embodiments, the cancer is breast cancer, prostate cancer, lung cancer, or colon cancer. In yet another embodiment, the epithelial cancer is non-small cell lung cancer, non-papillary renal cell carcinoma, cervical cancer, ovarian cancer (e.g., serous ovarian cancer), or breast cancer.

[0106] In some embodiments, the pharmaceutical compositions and methods comprising Compound A, Compound A or a salt thereof, provided herein may be used for the treatment of a wide variety of cancers, including tumors of the lung, prostate, breast, brain, skin, cervix, and testicular carcinomas. More specifically, the cancers and methods that can be treated in this disclosure include, but are not limited to, tumor types such as astrocytic, breast, cervix, colorectal, endometrial, esophageal, gastric, head and neck, hepatocyte, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. Other cancers include, for example, Cardiac sarcomas, for example, sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung cancer, for example, bronchogenic carcinoma (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrotoxic hamartoma, mesothelioma; The digestive tract, for example, the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), and large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); The urogenital system, for example, the kidneys (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, adenomatous tumor, lipoma); Liver, for example, liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer, for example, gallbladder cancer, ampullary cancer, bile duct cancer; Bone, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyofibroma, osteoid osteoma, and giant cell tumor; Nervous system, for example, skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma); Gynecology, for example, the uterus (endometrial cancer, uterine cancer, endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (carcinoma); Blood, for example, blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders (e.g., myelofibrosis and myeloproliferative neoplasms, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, molar dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal glands, for example, can be cited as a cause of neuroblastoma.

[0107] In some embodiments, the cancer includes a RAS mutation, such as the RAS mutation described herein. In some embodiments, the cancer includes a RAS G12C mutation (e.g., a KRAS G12C mutation). In some embodiments, the mutation is a G12C mutation and one or more mutations selected from the following: (a) The following KRAS variants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof. (b) The following HRAS variants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof, as well as (c) The following NRAS variants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof. or any combination of the above. In some embodiments, the cancer comprises at least two RAS mutations, a G12C mutation, and at least one mutation selected from the group consisting of G13C, G13D, G13S, G13V, Q61H, Q61K, Q61L, or a combination thereof. In some embodiments, the cancer is non-small cell lung cancer, and the RAS mutation comprises a KRAS mutation such as KRAS G12C. In some embodiments, the cancer is colorectal cancer, and the RAS mutation comprises a KRAS mutation such as KRAS G12C. In some embodiments, the cancer is pancreatic cancer, and the RAS mutation comprises a KRAS G12C mutation. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is colorectal cancer.

[0108] In some embodiments, the cancer includes an NRAS G12C mutation. In some embodiments, the cancer includes an HRAS G12C mutation. In some embodiments, the cancer includes both an NRAS G12C mutation and a KRAS G12C mutation.

[0109] Methods for detecting RAS mutations are known in the art. Such methods include, but are not limited to, direct sequencing, as well as the use of highly sensitive diagnostic assays (using CE-IVD markings), such as those described in, for example, Domagala, et al., Pol J Pathol 3:145-164 (2012) (the entire text of which is incorporated herein by reference), including TheraScreen PCR, AmoyDx, PNAClamp, RealQuality, EntroGen, LightMix, StripAssay, Hybcell plexA, Devyser, Surveyor, Cobas, and TheraScreen Pyro. See also, for example, WO2020 / 106640.

[0110] In some embodiments, cancer is caused by RAS mutations and STK11 LOF This includes KEAP1, EPHA5, or NF1 mutations, or combinations thereof. In some embodiments, the cancer is non-small cell lung cancer and includes the KRAS G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and includes the KRAS G12C mutation, STK11 LOF Mutations, including KEAP1 mutations. In some embodiments, the cancer is non-small cell lung cancer, with KRAS G12C mutation and STK11 LOF This includes mutations. In some embodiments, the cancer is non-small cell lung cancer, and the KRAS G12C mutation and STK11 LOF The mutation is included. In some embodiments, the cancer is colorectal cancer and contains the KRAS G12C mutation. In some embodiments, the cancer is pancreatic cancer and contains the KRAS G12C mutation. In some embodiments, the cancer is endometrial cancer and contains the KRAS G12C mutation. In some embodiments, the cancer is gastric cancer and contains the KRAS G12C mutation.

[0111] In some embodiments, a subject treated with compound A in the disclosed manner is a subject that has received at least one prior systemic cancer therapy (e.g., compound A is a second or third-line therapy). In some embodiments, a subject treated with compound A in the disclosed manner is a subject that has had disease progression after at least one prior systemic cancer therapy (i.e., compound A is a second-line therapy). In some embodiments, a subject treated with compound A in the disclosed manner is a subject that has had disease progression after at least two prior systemic cancer therapies (i.e., compound A is a third-line therapy). Prior systemic cancer therapy can be any therapy approved by a regulatory authority (e.g., FDA or EMA) as a given type and stage of cancer treatment. In some cases, prior systemic cancer therapy is a cancer therapy that is undergoing clinical trials but has not yet been approved by a regulatory authority. If a subject has received prior systemic cancer therapy, in some cases the subject has not received any systemic cancer therapy for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months prior to initiating therapy with compound A as disclosed herein.

[0112] In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering to the subject a composition comprising the subject an amount of compound A disclosed herein or a combination of compounds described herein, wherein the subject has one or more tumors that are resistant or unresponsive to treatment. In various embodiments, the subject has one or more tumors that are resistant or unresponsive to one or more treatments selected from the group consisting of surgery, radiation, chemotherapy, biological agents, small molecule, cell-based therapies, hormone therapy, and immunotherapy. In various embodiments, the treatment is standard therapy, first-line therapy, second-line therapy, or third-line therapy. In various embodiments, the subject has one or more tumors that have progressed between one or more treatments, and the treatment is standard therapy, first-line therapy, second-line therapy, or third-line therapy.

[0113] First-line therapy is defined as treatment administered to a patient with cancer who has received no prior treatment. Second-line therapy is defined as treatment administered to a patient with cancer who has previously received first-line therapy but has experienced disease progression during first-line treatment. Third-line therapy is defined as treatment administered to a patient with cancer who has previously received first and second-line therapy but has experienced disease progression during second-line treatment. Each specific type of cancer has first-line, second-line, and third-line therapies. First, second, and third-line therapies for each type of cancer are publicly known in the relevant art. In addition, FDA-approved drug labels indicate whether a particular drug is approved as a first, second, or third-line therapy.

[0114] In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering to the subject a composition comprising the amount of compound A disclosed herein or a combination of compounds described herein, wherein the subject is unable to tolerate standard, first-line, second-line, or third-line therapies. In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering to the subject a combination therapy comprising compound A or compound A, wherein the subject has experienced tumor recurrence after surgical resection of the primary tumor. In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering to the subject a composition comprising the amount of compound A disclosed herein or a combination of compounds described herein, wherein the subject has a tumor that cannot be surgically removed. In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering to the subject a composition comprising the amount of compound A disclosed herein or a combination of compounds described herein, wherein the subject has no available treatment options.

[0115] In some embodiments, cancer involves mutations in the RAS, and cancer is resistant to treatment with RAS(OFF) inhibitors, such as KRASG12C(OFF) inhibitors. As used herein, the term “resistant to treatment” refers to treatment of a disorder with a therapeutic agent where the therapeutic agent is ineffective or, although previously effective, its effectiveness has decreased over time. Resistance to treatment includes acquired and / or adaptive resistance to treatment, which refers to a decrease in the effectiveness of the treatment over the period that the subject is receiving the therapeutic agent. Acquired resistance to treatment may result from the acquisition of mutations in the target protein that render the treatment ineffective or less effective. Thus, resistance to treatment may persist even after discontinuation of the therapeutic agent. In particular, cancer may become resistant to treatment with RAS(OFF) inhibitors that reduce the effectiveness of the RAS(OFF) inhibitor. Measuring the decrease in the effectiveness of treatment depends on the disorder being treated, and such methods are known to those skilled in the art. For example, the effectiveness of cancer treatment may be measured by disease progression. Effective treatment may slow or halt disease progression. Cancers that are resistant to therapeutic agents, such as RAS(OFF) inhibitors, may not be able to slow or stop the progression of the disease.

[0116] In some embodiments, the dosage of compound A may be optionally administered to the subject with food, such as a standardized high-fat, high-calorie meal, or in a fasted state (no food or liquid intake except water for more than 10 hours). In one embodiment, the dosage of compound A is administered with or without food.

[0117] Patients receiving therapy are monitored for adverse events (AEs) during the course of therapy. Treatment-related AEs are AEs related to the medication. AEs occurring during treatment are AEs that occur in the patient receiving treatment that were not present before the start of therapy. In some cases, AEs occurring during treatment are not related to the treatment itself, or are suspected to be unrelated. AEs are characterized as one of five grades: Grade 1 is a mild AE, Grade 2 is a moderate AE, Grade 3 is a severe AE, Grade 4 is a life-threatening or disability-impairing AE, and Grade 5 is death related to the AE. In some cases, the patient does not exhibit any Grade 3 AEs related to treatment. In some cases, the patient does not exhibit any Grade 4 AEs related to treatment. In some cases, the patient does not exhibit any Grade 4 AEs related to treatment. In various cases, subjects do not exhibit treatment-related grade 3 or grade 4 adverse events for at least one month, or at least three months, after administration of compound A.

[0118] In various cases, subjects treated with compound A in the manner disclosed herein do not exhibit any dose-limiting toxicity (DLT) at the administered dose. DLT is any adverse event (AE) occurring during the first treatment cycle (days 1-21) of compound A that meets the following criteria and cannot be ruled out as being related to the drug.

[0119] In various cases, the subject of the disclosed method demonstrates a response to treatment. In some cases, subjects exhibit at least stable disease (SD) as a result of administration of compound A. In some cases, subjects exhibit at least a partial response (PR) as a result of administration of compound A. The response of subjects is assessed by criteria defined by RECIST 1.1, as discussed, for example, in Eisenhauer et al., Eur J Cancer, 45:228-247 (2009). A complete response (CR) is the disappearance of all target lesions, with any pathological lymph nodes reduced to less than 10 mm in the short axis. A partial response (PR) is a reduction of at least 30% of the total diameter of target lesions, with reference to the total diameter at baseline. Progressive disease is an increase of at least 20% of the total diameter of target lesions, with reference to the minimum total in the study (in the case of the minimum in the study, including the total at baseline), and in addition to a relative increase of 20%, there must be an absolute increase of at least 5 mm. A stable disease state is one in which there is neither sufficient contraction to qualify for a partial response (PR) nor sufficient increase to qualify for a progressive disease (PD). A controlled disease state is when the patient may alternate between exhibiting stable disease and partial responses. Tumor size can be measured by X-ray scan.

[0120] In certain embodiments, the method includes monitoring of regulated cardiac activity or function, such as QTc interval prolongation, during the course of the therapy disclosed herein. Furthermore, in certain embodiments, the subject may undergo screening for regulated cardiac activity or function prior to administration of the therapy disclosed herein. Non-limiting examples of methods for screening or monitoring regulated cardiac activity or function useful in the method disclosed herein include electrocardiogram (ECG), electrolyte level monitoring, echocardiography, stress testing, MRI, and any other testing techniques known in the art.

[0121] In various cases, the disclosed methods exclude subjects with congenital QT prolongation syndrome or concurrent QTc prolongation. In some embodiments, the methods include, in non-limiting cases, monitoring cardiac activity or function before administration, during concomitant use, and / or during the therapy disclosed herein, where clinically indicated, in subjects with bradyarrhythmia, electrolyte abnormalities, or concomitant drugs known to prolong the QT interval that cannot be avoided. In some embodiments, subjects do not have medically uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg; in France, systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg), congestive heart failure class 2 or higher as defined by the New York Heart Association, acute coronary syndrome (including unstable angina, coronary stenting or angioplasty, or bypass grafting within the past 6 months), myocardial infarction within the past 6 months, a history or evidence of a current uncontrolled, clinically significant, unstable arrhythmia, a history of congenital long QT syndrome or a prolonged corrected QT interval (QTc) greater than 470 milliseconds using the Fridericia formula (unless a pacemaker is implanted), or uncorrectable abnormalities of serum electrolytes (i.e., sodium, potassium, calcium, magnesium, phosphorus), or cardiac abnormalities such as a baseline left ventricular ejection fraction (LVEF) <50%. Generally, the mean of triple readings may be used to assess the QTc interval.

[0122] In some embodiments, the method involves administering the therapies disclosed herein to subjects who have discontinued or avoided concomitant use of products known to potentially prolong the QTc interval. In some embodiments, subjects may require drugs known to prolong the QTc, including but not limited to amiodarone, anagrelide, arsenic trioxide, azithromycin, chloroquine, chlorpromazine, cilostazol, ciprofloxacin, citalopram, disopyramide, dofetilide, donepezil, dronedarone, droperidol, erythromycin, escitalopram, flucainide, fluconazole, haloperidol, ibutilide, levofloxacin, methadone, moxifloxacin, ondansetron, oxaliplatin, pentamidine, pimozide, procainamide, propofol, quinidine, sevoflurane, sotalol, thioridazine, and vandetanib.

[0123] In one embodiment, the Disclosure provides a method for treating a subject having cancer (e.g., cancer involving the KRAS G12C mutation), the method generally comprising administering to the subject a composition containing about 200 mg to about 400 mg of compound A, the composition being administered to the subject twice daily, and the subject being monitored for QTc interval prolongation. In various cases in which a change in the QTc interval is detected, for example, if an absolute QTc value exceeds 500 ms or an increase of more than 60 ms from baseline is detected, the method further includes suspending administration of the composition containing compound A for a period sufficient to allow the QTc interval to become less than about 481 ms or return to baseline. In some embodiments, if the subject has a detection of treatment-related QTc prolongation, the method may include reducing the dose of compound A to the next lower dose level. In a non-limiting example, a subject receiving about 300 mg of compound A twice daily may have the dose reduced to about 250 mg of compound A twice daily. In another non-limiting example, a subject receiving approximately 250 mg of compound A twice daily could have their dose reduced to approximately 200 mg of compound A twice daily. In yet another non-limiting example, a subject receiving approximately 200 mg of compound A twice daily could have their dose reduced to approximately 150 mg of compound A twice daily. And in yet another non-limiting example, a subject receiving approximately 200 mg to 300 mg of compound A twice daily could have their dose reduced to approximately 200 to 400 mg of compound A once daily.

[0124] In one embodiment, the Disclosure provides a method for treating a subject having cancer (e.g., cancer involving the KRAS G12C mutation), the method generally comprising administering to the subject a composition comprising a certain amount of compound A disclosed herein. In some embodiments, the dosage of compound A disclosed herein may optionally be administered to the subject with food, such as a standardized high-fat, high-calorie diet, or on an empty stomach (no food or liquid intake except water for more than 10 hours). In one embodiment, the dose of compound A is administered with or without food. In some embodiments, the dose of compound A is administered without food. In some embodiments, no food is permitted for at least 4 hours after administration. In some embodiments, no food is permitted for at least 8 hours before administration. In some embodiments, no food is permitted for at least 8 hours before administration and no food is permitted for at least 4 hours after administration. In some embodiments, water is permitted only 1 hour before and / or 1 hour after administration.

[0125] Combination therapy Compositions comprising compound A and one or more therapeutic agents for use in the treatment of RAS-related diseases or disorders (e.g., cancer) are provided herein. In certain embodiments, the composition of the Disclosure comprises two or more RAS(ON) inhibitor therapies (e.g., compound A + RMC-6236). In certain embodiments, the composition of the Disclosure comprises the amounts of RAS(ON) inhibitor therapy and one additional therapeutic agent disclosed herein. In certain embodiments, the composition of the Disclosure comprises RAS(ON) inhibitor therapy and two additional therapeutic agents. In certain embodiments, the composition of the Disclosure comprises RAS(ON) inhibitor therapy and three additional therapeutic agents. In certain embodiments, the composition of the Disclosure comprises RAS(ON) inhibitor therapy and four or more additional therapeutic agents.

[0126] Pharmaceutical compositions comprising combinations thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients are also provided. Compositions comprising combinations of therapeutic agents may be used, as described herein, in methods of modulating the RAS (e.g., in subjects or cells) and in methods of treating RAS-related diseases and disorders (e.g., cancer). This disclosure provides, among other things, compositions, methods, and kits for treating or preventing RAS-related diseases or disorders.

[0127] Compound A disclosed herein may be administered before, after, or concurrently with one or more such additional therapies. When combined, the dosages of Compound A and one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) administered in the amounts disclosed herein provide a therapeutic effect (e.g., a synergistic or additive therapeutic effect). Compound A and any additional therapeutic agents, such as any additional therapeutic agents disclosed herein, may be administered together, such as in a single pharmaceutical composition, or separately. If administered separately, the administration may be simultaneous or sequential. Such sequential administration may have close or distant intervals between doses.

[0128] All references herein, whether expressly stated or not, are incorporated herein by reference to the drugs described herein, including the compounds or molecular structures disclosed herein.

[0129] a) RAS(ON) inhibitors The compositions and methods of the present disclosure comprise compound A + a RAS(ON) inhibitor. In some embodiments, the RAS(ON) inhibitor is a RAS(ON) multiselective inhibitor (e.g., RMC-6236, RMC-7977, RM-034, GFH547, ERAS-0015, or compound 6A of WO2024 / 067857). Exemplary RAS(ON) multiselective inhibitors useful in combination according to the present disclosure can be found in any one of the following patent applications: WO2024153208, WO2024149214, WO2024104364, WO2024067857, WO2024060966, WO2024017859, WO2024008834, WO20232402 63, WO2023025832, WO2022060836, WO2021091956, CN117720556, CN117720555, CN117720554, CN117534687, CN117534685, and CN117534684, each of these, including the compound structure disclosed in the said document, are incorporated herein by reference in their entirety.

[0130] In some embodiments, the RAS(ON) multiselective inhibitor is RMC-6236. [ka]

[0131] In some embodiments, the RAS(ON) multiselective inhibitor is compound 6A of WO2024 / 067857: [ka]

[0132] Some embodiments of combinations including RAS(ON) therapy include a composition comprising a RAS(ON) variant-selective inhibitor. In some embodiments, the RAS(ON) variant-selective inhibitor is a RAS(ON)G12D selective inhibitor. In some embodiments, the RAS(ON) variant-selective inhibitor is a RAS(ON)G13C selective inhibitor. In some embodiments, the RAS(ON) variant-selective inhibitor is a RAS(ON)Q61H selective inhibitor. In some embodiments, the RAS(ON) variant-selective inhibitor is a RAS(ON)G12V selective inhibitor. In some embodiments, the RAS(ON) variant-selective inhibitor is a RAS(ON)G13D selective inhibitor. Useful RAS(ON) mutant-selective inhibitors according to the methods of this disclosure can be found in any one of the following patent applications: WO2024102421, WO2023240263, WO2023133543, WO2023015559, WO2023086341, WO2023208005, WO2023060253, WO2022235870, WO202223586 4, WO2021091967, WO2021091982, WO2021108683, WO2020132597, International Patent Application Nos. PCT / US2024 / 023208, PCT / US2024 / 023272, and PCT / US2024 / 030993, each of which includes the compound structures disclosed herein, are incorporated herein by reference in their entirety.

[0133] In some embodiments, a useful RAS(ON) mutant-selective inhibitor according to this disclosure is RMC-9805. [ka]

[0134] In some embodiments, the combination therapy comprising compound A may comprise one or more RAS(ON) inhibitors, for example, compound A + one or more RAS(ON) multiselective inhibitors and / or one or more RAS(ON) mutant-selective inhibitors.

[0135] The synthesis of RAS(ON) inhibitors is understood by those skilled in the art, as follows: known synthetic methods in the field of synthetic organic chemistry, or variations thereof, for example, WO2024008610, WO2024102421, WO2023240263, WO2023133543, WO2023015559, WO2023086341, WO2023208005, WO2023232776, WO As described in 2023060253, WO2022235870, WO2022235864, WO2021091967, WO2021091982, WO2021108683, WO2020132597, International Patent Application Nos. PCT / US2024 / 023208, PCT / US2024 / 023272, and PCT / US2024 / 030993, this is already known.

[0136] b) RAS / MAPK inhibitors The compositions and methods described herein may include compound A in combination with one or more RAS / MAPK pathway inhibitors. The RAS / MAPK pathway refers to a signal transduction cascade downstream of various cell surface growth factor receptors, where activation of RAS (and its diverse isoforms and allotypes) is a central event driving various cellular effector events that determine cell proliferation, activation, differentiation, mobility, and other functional properties. SHP2 transmits a positive signal from the growth factor receptor to the RAS activation / deactivation cycle, which is regulated by guanine nucleotide exchange factors (GEFs such as SOS1) that load GTP into RAS to produce functionally active, GTP-bound RAS, and GTP-accelerating proteins (GAPs such as NF1) that facilitate the termination of the signal by converting GTP to GDP. The GTP-bound RAS produced by this cycle transmits essential positive signals to a series of serine / threonine kinases, including RAFs and MAP kinases, from which further signals extend to various cellular effector functions. In some embodiments, therapeutic agents that can be combined with RAS(ON) inhibitors are inhibitors of the MAP kinase (MAPK) pathway (or "MAPK inhibitors"). MAPK pathway inhibitors include, but are not limited to, one or more MAPK pathway inhibitors described in Cancers (Basel) 2015 Sep;7(3):1758-1784. For example, MAPK inhibitors include trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132, vemurafenib, pimacertib, TAK733, RO4987655 (CH4987655), CI-1040, PD-0325901, CH5126766, MAP855, AZD6244, refametinib (RDEA 119 / BAY 86-9766), GDC-0973 / XL581, AZD8330 (ARRY-424704 / ARRY-704), RO5126766 (Roche, PLoS One. 2014 Nov). One or more of the following may be selected: 25;9(11), and GSK1120212 (or JTP-74057, Clin Cancer Res. 2011 Mar 1;17(5):989-1000).MAPK pathway inhibitors may include PLX8394, LXH254, GDC-5573, or LY3009120. MAPK pathway inhibitors may also include PI3Kα:RAS disruptors such as BBO-10203.

[0137] i) RAS(OFF) inhibitors and RAS(OFF) degrading agents The compositions and methods described herein may include compound A in combination with one or more RAS(OFF) inhibitors. Numerous mutant-selective and pan-KRAS inhibitors have been disclosed and are known in the art. RAS(OFF) inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein. RAS(OFF) inhibitors are designed to inhibit RAS activity by targeting various regions of the RAS protein in an inactive state (GDP-bound state) and blocking its activation and downstream signaling.

[0138] In some embodiments, the RAS(OFF) inhibitor is a KRAS(OFF) inhibitor having a molecular weight of less than 700 Da. The term "KRAS(OFF) inhibitor" refers to any RAS(OFF) inhibitor that binds to KRAS at its GDP-bound "off" position. In some embodiments, the KRAS(OFF) inhibitor is a KRAS G12C It is specific to the mutation. KRAS G12C (OFF) inhibitors are KRAS G12C Using covalent groups that allow for selective targeting of mutant proteins, many such inhibitors contain a pyrimidine core. (KRAS) G12C (OFF) All inhibitors are KRAS G12C KRAS targets identical cysteine ​​residues within mutant proteins, inducing a structural change that fixes the protein in an inactive state. G12C(OFF) inhibitors include AMG510 (sotrasib), MRTX849 (adagrasib), MRTX1257, GDC-6036 (divalasib), JDQ443 (opnurasib), ERAS-3490, LY3537982 (olomorasib), BI1823911, BPI-421286, JAB-3312, JAB-21000, JAB-21822 (gresira). This includes, but is not limited to, KRAS(OFF) inhibitors such as D-1553 (Galsoracib), D3S-001, HYP-209PTSA, HBI-2438, HS-10370, MK-1084, YL-15293, BBO-8520 (ON / OFF inhibitor), FMC-376 (ON / OFF inhibitor), GEC255, BBO-11818, and GFH925 (IBI351). In some embodiments, the KRAS(OFF) inhibitor is selected from AMG510 and MRTX849. In some embodiments, the KRAS(OFF) inhibitor is AMG510. In some embodiments, the KRAS(OFF) inhibitor is selected from BPI-421286, JNJ-74699157 (ARS-3248), LY3537982, MRTX1257, ARS853, ARS1620, or GDC-6036.

[0139] In some embodiments, the KRAS(OFF) inhibitor is KRAS G12D It is specific to the mutation. Many KRAS G12D (OFF) inhibitors start with RAS G12C It was developed using (OFF) inhibitors and therefore shares a G12C inhibitor skeleton when combined with other chemical components such as piperazine compounds. KRAS G12D Non-exclusive examples of (OFF) inhibitors include MRTX1133, MRTX282, JAB-22000, ERAS-4, ERAS-5024, HRS-4642, BI-2852, BI-2852, ASP3082, TH-Z827, TH-Z835, TSN1611, QTX-3046, GFH375 (VS-7375), INCB161734, and KD-8.

[0140] In some embodiments, the small molecule RAS(OFF) inhibitor is KRAS G12V It is specific to the mutation. In some embodiments, the small molecule RAS(OFF) inhibitor is KRAS G13D It is specific to the mutation. In some embodiments, small molecule RAS(OFF) inhibitors are pan-KRAS(OFF) inhibitors.

[0141] In some embodiments, references to the term RAS(OFF) inhibitor include any such RAS(OFF) inhibitor disclosed in any one of the following patent applications: WO2024138486, WO2024138206, WO2024138052, WO2024131829, WO2024125642, WO2024125600, WO2024123913, WO2024123102, WO2024120433, WO2024120419, WO2024123913, WO2024085661, WO202408325 8, WO2024083256, WO2024083246, WO2024083168, WO2024078555, WO2024076674, WO2024076672, WO2024076670, WO2024067714, WO2024067575, WO202 4064335, WO2024063578, WO2024063576, WO2024061370, WO2024061333, WO2024061267, WO2024056063, WO2024055112, WO2024054926, WO2024054647 , WO2024054625, WO2024051763, WO2024051721, WO2024050742, WO2024050640, WO2024046406, WO2024046370, WO2024045066, WO2024044667, WO202 4044649, WO2024044334, WO2024041621, WO2024041606, WO2024041589, WO2024041573, WO2024040131, WO2024040109, WO2024040080, WO2024036270 , WO2024034657, WO2024034593, WO2024034591, WO2024034123, WO2024032747, WO2024032704, WO2024032703, WO2024032702, WO2024031088, WO2024 030647, WO2024030633, WO2024029613, WO2024022507, WO2024022444, WO2024020159, WO2024019103, WO2024017859, WO2024017392, WO2024015731,WO2024015262、WO2024012456、WO2024009191、WO2024008179、WO20240081 78、WO2024008068、WO2024006445、WO2024006424、WO2024002373、WO202328 7896, WO2023287730, WO2023284881, WO2023284730, WO2023284537, WO2023283933, WO2023283213, WO2023280280, WO2023280136, WO2023280026, WO2 023278600, WO2023274383, WO2023327324, WO2023246914, WO2023246903, WO2023246777, WO2023244713, WO2023244615, WO2023244604, WO202324460 0, WO2023244599, WO2023230190, WO2023226630, WO2023225302, WO2023225252, WO2023220421, WO2023219941, WO2023217148, WO2023215802, WO2023 215801、WO2023213269、WO2023212548、WO2023208005、WO2023205719、WO2 023199180、WO2023198191、WO2023197984、WO2023190748、WO2023185864、W O2023183755, WO2023183585, WO2023179703, WO2023179629, WO2023173017, WO2023173016, WO2023173014, WO2023172737, WO2023171781, WO2023159 087, WO2023159086, WO2023154766, WO2023152255, WO2023151674, WO2023151621, WO2023150394, WO2023150284, WO2023143623, WO2023143605, WO20 23143352, WO2023143352, WO2023143312, WO2023141570, WO2023141300, WO2023138662, WO2023138601, WO2023138589, WO2023138524, WO2023133183WO2023133181, WO2023130012, WO2023125989, WO2023125627, WO2023122662, WO2023122154, WO2023120742, WO2023119677, WO2023117681, WO202311 6934, WO2023116895, WO2023114733, WO2023105491, WO2023104018, WO2023103906, WO2023103523, WO2023101928, WO2023099624, WO2023099624, WO2 023099620, WO2023099612, WO2023099608, WO2023099592, WO2023098832, WO2023098425, WO2023097227, WO2023081840, WO2023081476, WO202307842 4、WO2023077441、WO2023072297、WO2023072188、WO2023066371、WO2023064857、WO2023061463、WO2023061294、WO2023057985、WO2023056951、WO2023 056421、WO2023051586、WO2023049697、WO2023046135、WO2023045960、WO2 023041059、WO2023041059、WO2023040989、WO2023040513、WO2023039240、W O2023039020, WO2023036282, WO2023034290, WO2023030517, WO2023030495, WO2023030385, WO2023030495, WO2023030517, WO2023030685, WO2023030 687, WO2023034290, WO2023036282, WO2023039240, WO203020347, WO2023025116, WO2023287896, WO2023287730, WO2023284881, WO2023284730, WO202 3284537, WO2023283933, WO2023283213, WO2023280280, WO2023280136, WO2023280026, WO2023278600, WO2023274383, WO2023327324, WO2023040989WO2023039240, WO2023039020, WO2023036282, WO2023034290, WO2023030517, WO2023030495, WO2023030385, WO2023025116, WO2023020523, WO20230 20521, WO2023020519, WO2023020518, WO2023020347, WO2023018812, WO2023018810, WO2023018809, WO2023018699, WO2023014979, WO2023014006, W O2023004102, WO2023003417, WO2023001141, WO2023001123, WO2022271658, WO2022269508, WO2022266167, WO2022266069, WO2022266015, WO202226 5974, WO2022261154, WO2022261154, WO2022251576, WO2022251296, WO2022237815, WO2022232332, WO2022232331, WO2022232320, WO2022232318, WO2 022223037, WO2022221739, WO2022221528, WO2022221386, WO2022216762 (e.g., compound 44 or compound 66a), WO2022212894, WO2022192794, WO2022192790, WO2022188729, WO2022187411, WO2022184178, WO2022173870, WO2022173678, WO2022135346, WO2022133731, WO2022133038, WO2022133345, WO202213220 0, WO2022119748, WO2022109485, WO2022109487, WO2022066805, WO2022002102, WO2022002018, WO2021259331, WO2021257828, WO2021252339, WO202 1248095, WO2021248090, WO2021248083, WO2021248082, WO2021248079, WO2021248055, WO2021245051, WO2021244603, WO2021239058, 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8143315、WO2018140600、WO2018140599、WO2018140598、WO2018140514、WO2018140513、WO2018140512、WO2018119183、WO2018112420、WO2018068017、WO2018064510、WO2017201161、WO2017172979、WO2017100546、WO2017087528、WO2017058807、WO2017058805、WO2017058728、WO2017058902、WO2017058792、WO2017058768、WO2017058915、WO2017015562、WO2016168540、WO2016164675、WO2016049568、WO2016049524、WO2015054572、WO2014152588、WO2014143659、WO2013155223、CN118221700、CN118221699、CN118221698、CN118221685、CN118126064、CN118078802、CN118078801、CN118005656、CN117986263、CN117986263、CN117946135、CN117924327、CN117903117、CN117800990、CN117800989、CN117800976、CN117736226、CN117683051、CN117645627、CN117624194、CN117624190、CN117586280、CN117486901、CN117466917、CN117462688、CN117362315、CN117327102、CN117327094、CN117327074、CN117285590、CN117263959、CN117247382、CN117186095、CN117164605、CN116969977、CN116925075、CN116891489、CN116731045、CN116731044、CN116554208、CN116514846、CN116478184、CN116478141、CN116410145、CN116375742、CN116354988、CN116332948、CN116332938、CN116327956、CN116262759、CN116217592、CN116199703、CN116162099、CN116143806、CN116143805、CN116120315、CN116102559、CN115960105、CN115894520、CN115872979、CN115850267、CN115785199、CN115785124、CN115724842、CN115724842、CN115721720、CN115716840、CN115703775、CN115611923、CN115611898、CN115583937、CN115572278、CN115557949、CN115521312、CN115504976、CN115490709、CN115466272、CN115433183、CN115433179、CN115403575、CN115385938、CN115385937、CN115385912、CN115381786、CN115368383、CN115368382、CN115368381、CN115353506、CN115322158、CN115304623、CN115304602、CN115197245、CN115181106、CN114989195、CN114989166、CN114989147、CN114920741、CN114920739、CN114907387、CN114874234、CN114874201、CN114716436、CN114716435、CN114685532、CN114685460、CN114591319、CN114539293、CN114539286、CN114539246、CN114437107、CN114437084、CN114409653、CN114380827、CN114195804、CN114195788、CN114437107、CN114409653、CN114380827、CN114195804、CN114057776、CN114057744、CN114057743、CN113999226、CN113980032、CN113980014、CN113960193、CN113929676、CN113754653、CN113683616、CN113563323、CN113527299、CN113527294、CN113527293、CN113493440, CN113429405, CN113321654, CN113248521, CN113087700, CN113024544, CN1130042 69, CN112920183, CN112778284, CN112390818, CN112390788, CN112300196, CN112300194, CN1123 00173, CN112225734, CN112142735, CN112110918, CN112094269, CN112047937, CN109574871, or EP4389751, each of these, including the RAS compound structure disclosed in the said document, is specifically incorporated herein by reference.

[0142] In some embodiments, references to the term RAS(OFF) inhibitor refer to a pan-KRAS inhibitor selected from any one disclosed below: WO2024119277, WO2024120433, WO2024115890, WO2024112654, WO2024104453, WO2024104425, WO2024107686, WO2024104453, WO2024103010, WO2024085661, WO2024083246, WO2024083168, WO2024067575, WO2024 064335, WO2024063578, WO2024063576, WO2024051852, WO2024051763, WO2024046370, WO2024044667, WO2024041621, WO2024041606, WO2024041589, WO2024040131, WO2024040109, WO2024032747, WO2024032704, WO2024032703, WO2024032702, WO2024031088, WO2024030647, WO2024030633, WO202401 5262, WO2024009191, WO2024008068, WO2024002373, WO2023287896, WO2023274324, WO2023246914, WO2023246777, WO2023230190, WO2023215802, WO 2023215801, WO2023197984, WO2023190748, WO2023183585, WO2023179703, WO2023173017, WO2023173016, WO2023173014, WO2023172737, WO20231547 66, WO2023143352, WO2023143312, WO2023138589, WO2023133183, WO2023122662, WO2023114733, WO2023099624, WO2023099623, WO2023099612, WO202 3099608, WO2023099592, WO2023097227, WO2023064857, WO2023056421, WO2023049697, WO2023046135, WO2023039240, WO2023034290, WO2023020523,WO2023020521, WO2023020519, WO2023020518, WO2023001123, WO2022271823, WO2022261210, WO2022258974, WO20222 56459, WO2022250170, WO2022248885, WO2022228543, WO2022216762, WO2022072783, WO2016161361, KR20240041720, K R20240041719, CN118221700, CN118126064, CN117924327, CN117946135, CN117800990, CN117800989, CN117683051, CN117486901, CN117263959, CN116969977, or CN116332948, each of these, including the compound structure disclosed in the said document, are incorporated herein by reference in their entirety. In some embodiments, a combination therapy comprising compound A may include one or more additional RAS inhibitors, such as pan-KRAS inhibitors. In some embodiments, a combination comprising pan-KRAS inhibitor therapy includes ERAS-4001. In some embodiments, the pan-KRAS inhibitor is a pan-KRAS inhibitor in a patent application filed in the name of Medshine Discovery, Inc. In some embodiments, combinations of pan-KRAS inhibitor therapy include BGB-53038, BBO-11818, YL-17231, QTX3034, ABT-200, ADT-1004, AN9025, OC211, JAB-23425, BI-2865, BI-2493, ABREV01, A2A-03, or PF-07934040.

[0143] In any embodiment using a combination with the RAS(OFF) inhibitor described herein, an RAS(OFF) degrading agent that targets the OFF state of the RAS may be used. These degrading agents are known in the art. RAS degrading agents can be found, for example, in one or more of the following applications: WO2024131777, WO2024120424, WO2024119278, WO2024118966, WO2024118960, WO2024083258, WO2024083256, WO2024055112, WO2024054625, WO2024050742, WO2024044334, WO2024040080, WO2024034657, WO2024034593, WO2024034591, WO20 24034123, WO2024029613, WO2024020159, WO2024019103, WO2024017392, WO2023185864, WO2023171781, WO2023141570, WO2023138524, WO2023130012, WO2023116934, WO2023099620, WO2023081476, WO2023077441, CN118126040, and CN115785199, each of these in whole, are incorporated herein by reference.

[0144] In some embodiments, RAS(OFF) inhibitors are peptide-based inhibitors. For example, peptide-based RAS(OFF) inhibitors have been developed that target specific regions of the RAS protein, such as the switch II region or the RAS effector interface. Non-limiting examples include the K-Ras binding peptide (Krpep-2d), the Ras inhibitor peptide (RasIn), and LUNA18 (NCT05012618). Peptide-based RAS(OFF) inhibitors are a class of compounds that target the RAS protein by interfering with its interaction with downstream effectors or other signaling proteins. These inhibitors are typically designed to mimic the binding motif of RAS interacting proteins or other RAS effectors, such as RAF or PI3K. By binding to RAS at the same site as these effectors, peptide-based inhibitors can effectively compete with these proteins and block the activation of downstream signaling pathways. For example, see WO2024101402, WO2024101386, WO2023214576, WO2023140329, WO2022234853, WO2022234852, WO2022234851, and WO2022234639, each of which is incorporated herein by reference in whole.

[0145] Peptide-based RAS(OFF) inhibitors can be further classified into two main categories: those targeting the RAS-effector interface and those targeting other regions of the RAS protein. Peptide-based inhibitors targeting the RAS-effector interface are designed to bind to the switch region of RAS, which is important in interactions with downstream effectors such as RAF or PI3K. These inhibitors typically contain amino acid residues similar to those found in the binding motif of RAS-interacting proteins or effectors, and are often designed to form hydrogen bonds or other interactions with key residues on the RAS surface.

[0146] Peptide-based RAS(OFF) inhibitors that target other regions of the RAS protein are typically designed to interfere with other interactions that are important for RAS activation or signaling. For example, some peptide-based inhibitors are designed to bind to the hypervariable region of the RAS, which is thought to play a role in protein membrane localization and fixation. By binding to this region, peptide-based inhibitors may block the proper localization of the RAS to the plasma membrane, which is necessary for activation and signaling.

[0147] Several common motifs have been identified as important for the binding of RAS-interacting proteins and effectors and are often used in the design of peptide-based inhibitors. One example is the RAF-binding domain (RBD), found in many RAS-interacting proteins and important for the interaction between RAS and downstream effectors such as RAFs. The RBD contains a conserved amino acid sequence (Arg-Xaa-Arg) that is important for binding to RAS, and this motif has been incorporated into several peptide-based inhibitors designed to disrupt RAS-RAF interactions. Another example is the RAS-binding domain (RBD) of PI3K, which is important for the interaction between RAS and its downstream effector. The PI3K RBD contains several conserved amino acid residues (such as Arg-Arg-Trp) that are important for binding to RAS, and these motifs have been used in the design of peptide-based inhibitors targeting RAS-PI3K interactions. Other common motifs used in peptide-based RAS(OFF) inhibitors include sequences that mimic the structure of the Ras-binding domain (RBD) of other RAS-interacting proteins such as RalGDS and SOS, as well as the switch region of RAS itself. These motifs are typically used to optimize the binding affinity and selectivity of the inhibitor for a desired target protein or interaction.

[0148] In some embodiments, RAS(OFF) inhibitors are antibodies or antigen-binding peptides specific to RAS(OFF). For example, antibodies have been developed that bind to specific regions of the RAS protein, such as the switch II region or the RAS effector interface. For instance, several antibodies have been developed that target the switch region of the RAS protein, which is crucial for the activation of these proteins and their interaction with downstream effectors. By binding to the switch region, these antibodies can block the conformational changes necessary for RAS activation and downstream signaling. Another approach involves the use of antibodies that target RAS-interacting proteins or downstream effectors, such as RAF or PI3K. By binding to the target protein, these antibodies can disrupt the RAS-dependent signaling pathway, potentially inhibiting the proliferation and survival of cancer cells. Additionally, several antibodies have been developed that can induce the internal translocation and degradation of RAS proteins, leading to their depletion and inhibition of downstream signaling. For example, several antibodies have been developed that recognize the unique structures of mutant RAS proteins and target them for degradation via the ubiquitin-proteasome pathway. Non-exclusive examples of KRAS(OFF)-specific inhibitory antibodies include anti-p21ser and K27(DARPin) (see, for example, Khan et al, Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118570). See, for example, WO2024136608 and WO2024111590, each of which is incorporated herein by reference in whole.

[0149] ii) SOS1 inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more SOS1 inhibitors. The SOS1 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the SOS1 inhibitors are one or more of RMC-5845, RMC-4948, RMC-0331, BI-1701963, BI-3406, SDR5, MRTX-0902, ZG2001, and BAY-293. In some embodiments, references to the term SOS1 inhibitor include any such SOS1 inhibitor disclosed in any one of the following patent applications: WO2023109929, WO2023059597, WO2023029833, WO2023041049, WO2023022497, WO2022157629, WO2022184116, WO2022170952, WO2022170917, WO2022171184, WO2 022161461, WO2022121813, WO2022028506, WO2022139304, WO2021228028, WO2019122129, CN115215847, CN115028644, CN114685488, CN111393519, CN115677702, and CN115806560, each of these, including the compound structures disclosed in the said documents, are incorporated herein by reference in their entirety.

[0150] iii) SHP inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more SHP inhibitors. The SHP inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the SHP inhibitor is an inhibitor of SHP1. In some embodiments, the SHP inhibitor is an inhibitor of SHP2. In some embodiments, the SHP1 inhibitor is SB6299, also known as DA-4511. In some embodiments, the SHP2 inhibitor is one or more of SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, or BBP-398. In some embodiments, references to the term SHP2 inhibitor include any such SHP2 inhibitor disclosed in any one of the following patent applications: WO2023282702, WO2023280283, WO2023280237, WO2023018155, WO2023011513, WO2022271966, WO202227196 4, WO2022271911, WO2022259157, WO2022242767, WO2022241975, WO2022237676, WO2022237367, WO2022237178, WO2022235822, WO20222084008, WO2022135568, WO2022063190, WO2022043865, WO 2022042331, WO2022033430, WO2022017444, WO2022007869, WO2021259077, WO2021249449, WO20 21249057, WO2021244659, WO2021218755, WO2021176072, WO2021171261, WO2021149817, WO20211 48010, WO2021147879, WO2021143823, WO2021143701, WO2021143680, WO2021281752, WO20211213 97, WO2021119525, WO2021115286, WO2021110796, WO2021088945, WO2021073439, WO2021061706,WO2021061515、WO2021043077、WO2021033153、WO2021028362、WO2021033153、WO2021028362、WO2021018287、WO2020259679、WO2020249079、WO2020210384、WO2020201991、WO2020181283、WO2020177653、WO2020165734、WO2020165733、WO2020165732、WO2020156243、WO2020156242、WO2020108590、WO2020104635、WO2020094104、WO2020094018、WO2020081848、WO2020073949、WO2020073945、WO2020072656、WO2020065453、WO2020065452、WO2020063760、WO2020061103、WO2020061101、WO2020033828、WO2020033286、WO2020022323、WO2019233810、WO2019213318、WO2019183367、WO2019183364、WO2019182960、WO2019167000、WO2019165073、WO2019158019、WO2019152454、WO2019051469、WO2019051084、WO2018218133、WO2018172984、WO2018160731、WO2018136265、WO2018136264、WO2018130928、WO2018129402、WO2018081091、WO2018057884、WO2018013597、WO2017216706、WO2017211303、WO2017210134、WO2017156397、WO2017100279、WO2017079723、WO2017078499、WO2016203406、WO2016203405、WO2016203404、WO2016196591、WO2016191328、WO2015107495、WO2015107494、WO2015107493、WO2014176488、WO2014113584、CN115677661、CN115677660、CN115611869、CN115521305、CN115490697、CN115466273, CN115394612, CN115304613, CN115304612, CN115300513, CN11519 7225, CN114957162, CN114920759, CN114716448, CN114671879, CN114539223, CN1 14524772, CN114213417, CN114195799, CN114163457, CN113896710, CN11324852 1, CN113248449, CN113135924, CN113024508, CN112920131, CN112823796, CN1124 09334, CN112402385, CN112174935, 111848599, CN111704611, CN111393459, CN111265529, CN110143949, CN108113848, US11179397, US11044675, US11034705, US11033547, US11001561, US10988466, US10954243, US10934302, or US10858359, each of these, including the compound structure disclosed in the said document, is specifically incorporated herein by reference.

[0151] iv) MEK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more MEK inhibitors. The MEK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the MEK inhibitor is one or more of pimacertib, IMM-1-104, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation that is a class I MEK1 mutation selected from D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N. In some embodiments, references to the term MEK inhibitor include any such MEK inhibitor disclosed in any one of the following patent applications: WO2022221866, WO2022125941, WO2022208391, WO2022015736, WO2022177557, WO2021018866, WO2021069486, WO2021142144, WO2021168283, WO2021 234097, WO2019076947, WO2018233696, WO2016188472, WO2014063024, WO2013019906, WO2011047238, WO2007044515, US2023032403, and CN115813930, each of these, including the compound structures disclosed in the said documents, are incorporated herein by reference in their entirety.

[0152] v) RAF inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more RAF inhibitors. The RAF inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agent described herein. In some embodiments, the RAF inhibitor is VS-6766 or BTDX-4933. In some embodiments, the RAF inhibitor is a BRAF inhibitor. Examples of BRAF inhibitors that may be used in combination with compound A include Vs6766, IK-595, vemurafenib, dabrafenib, and encorafenib. BRAF may include class 3 BRAF mutations. In some embodiments, a class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H, P367R, V459L, G466V, G466E, G466A, S467L, G469E, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, G596R, and A762E. In some embodiments, references to the term RAF inhibitor include any such RAF inhibitor disclosed in any one of the following patent applications: WO2023076991, WO2022226626, WO2022226261, WO2019084459, WO2018203219, WO201851306, WO2017212442, WO2015075483, WO2013134243, WO2013134298, WO2011047238, WO20110 25965, WO2011025947, WO2011025951, WO2011025940, WO2011025938, WO2010065893, WO2009016460, WO2009130015, WO2009111278, WO2009111279, WO2008028141, and WO2006024834, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0153] (co) ERK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more ERK inhibitors. The ERK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the ERK inhibitor is an ERK1 / 2 inhibitor such as ERAS-007. In some embodiments, the ERK inhibitor is an ERK5 inhibitor. In some embodiments, the ERK inhibitor is one or more of ASTX-029 or I-75. In some embodiments, references to the term ERK inhibitor include any such ERK inhibitor disclosed in any one of the following patent applications: WO2023076305, WO2022259222, WO2022221547, WO2021110169, WO2021110168, WO2021252316, WO2020102686, WO2020228817, WO2020107987, WO2019233456, WO2019233457, WO20160255 61, WO2016192063, WO2016106029, WO2016106009, WO2015051341, WO2014124230, WO2014052563, WO2011041152, WO200910550, WO2008153858, CN114315837, CN115057860, CN107973783, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0154] vii) MAPK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more mitogen-activated protein kinase (MAPK) inhibitors. The MAPK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the MAPK inhibitor is a p38 MAPK inhibitor or a MAP3K8 inhibitor. In some embodiments, the MAPK inhibitor is one or more of chilpicertive (GS-4875) and neframapidomod (VX-745). In some embodiments, references to the term MAPK inhibitor include any such MAPK inhibitor disclosed in any one of the following patent applications: WO2016029263, CN114767674, CN115850179, and CN1743006, each of which includes the compound structures disclosed in such documents, each of which is specifically incorporated herein by reference.

[0155] In some embodiments, the therapeutic agent that can be combined with compound A is a MAP2K4 inhibitor. A non-limiting example of a MAP2K4 inhibitor useful according to this disclosure is HRX-0233.

[0156] c) Kinase inhibitors The compositions and methods described herein may include compound A in combination with one or more kinase inhibitors. Tyrosine kinases and serine / threonine kinases play important roles in various cellular processes such as cell signaling, proliferation, and differentiation. Kinase inhibitors known in the art have been developed as therapies for various types of cancer, in addition to therapies for conditions such as neurodegenerative diseases, autoimmune diseases, and inflammation.

[0157] i) PKA inhibitors In some embodiments, the compositions and methods described herein may comprise one or more protein kinase A (PKA) inhibitors. The PKA inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agent described herein. In some embodiments, the PKA inhibitor is H89. In some embodiments, references to the term PKA inhibitor include any such PKA inhibitor disclosed in any one of the following patent applications: CN106620678 and CN114632155, each of which comprises the compound structure disclosed in said document, which is specifically incorporated herein by reference.

[0158] ii) FAK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more focal adhesion kinase (FAK) inhibitors. The FAK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the FAK inhibitors are one or more of BI853520, defactinib, GSK2256098, PF-00562271, and VS-4718. In some embodiments, references to the term FAK inhibitor include any such FAK inhibitor disclosed in any one of the following patent applications: WO2022152315, WO2021098679, WO2020135442, WO2020191448, WO2012022408, WO2013134353, WO2012110774, WO2010062578, CN111072571, and KR101691536, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0159] iii) ROCK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more Rho-related coiled-coil-containing protein kinase (ROCK) inhibitors. The ROCK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agent described herein. In some embodiments, the ROCK inhibitor is GSK269962A. In some embodiments, references to the term ROCK inhibitor include any such ROCK inhibitor disclosed in any one of the following patent applications: WO2023051753, WO2022237892, WO2022012409, WO2021093795, WO2021214200, WO2020177292, WO202011751, WO2019014304, WO2019179525, WO2019089868, WO2019014300, WO2018108156, WO2018009627, WO2018009625, WO2018009622, WO2017123860, W O2017205709, WO2016112236, WO2014068035, WO2013030367, WO2012146724, WO2012067965, WO2011107608, CN108129453, CN108191821, CN110917352, CN108558823, CN108047193, CN107973777, CN108047197, CN108129448, CN115869304, and GB202214708, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0160] iv) MSK1 inhibitors In some embodiments, the compositions and methods described herein may comprise compound A in combination with one or more mitogens and stress-activated kinase (MSK1) inhibitors. The MSK1 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the MSK1 inhibitor is one or more of SB-747651A, SB747651A, Ro320432, CGP57380, GSK2830371, SR1664, LY-3214996, PFI-4, MSC-2363318A, and AS601245.

[0161] v) RSK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more ribosomal S6 kinase (RSK) inhibitors. The RSK1 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agent described herein. In some embodiments, the RSK inhibitor is one or more of BI-D1870, LJH685, SL0101-1, FMK, BRD7389, BIX02565, LJI308, LJI308-S, LJI308-1, and LJH685-S. In some embodiments, the RSK inhibitor is PMD-026. In some embodiments, references to the term RSK inhibitor include any such RSK inhibitor disclosed in any one of the following patent applications: WO2021249558, WO2020165646, WO2017141116, and CN113801139, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0162] vi) ALK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more anaplastic lymphoma kinase (ALK) inhibitors. The ALK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the ALK inhibitor is one or more of crizotinib (Zalkoli), ceritinib (Zykadia), alectinib (Alecensa), brigatinib (Alumbrig), lorlatinib (Lorbrena), ensartinib (X-396), TAE684, ASP3026, TPX-0131, LDK378 (ceritinib analog), CEP-37440, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Examples of adding ALK kinase inhibitors are described in Examples 3-39 of WO05016894. In some embodiments, references to the term ALK inhibitor include any such ALK inhibitor disclosed in any one of the following patent applications: WO2019142095, WO2019179482, WO2018130928, WO2018127184, WO2017101803, WO2016192132, WO2014100431, WO2012082972, CN111138492, CN110526914, CN109836415, CN105801603, CN107987056, and CN105878248, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0163] d) Receptor tyrosine kinase inhibitors The compositions and methods described herein may include compound A in combination with one or more receptor tyrosine kinase inhibitors. Receptor tyrosine kinase (RTK) inhibitors are a type of molecule (e.g., small molecules, antibodies, and nucleic acids) that binds to receptor tyrosine kinases or their ligands and blocks their activity. RTKs are proteins found on the surface of cells and play important roles in cell signaling and proliferation, and have been developed as therapeutic agents for a variety of diseases, including cancer, diabetes, and autoimmune disorders. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor such as afatinib.

[0164] i) EGFR inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more EGFR inhibitors. The EGFR inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zaltumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br.J. Cancer 1993, 67:247-253, Teramoto et al., Cancer 1996, 77:639-645, Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318, Huang et al., 1999, Cancer Res. 15:59(8):1935-40, and Yang et al., Cancer Res. 1999, 59:1236-1243. EGFR inhibitors can be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999), or Mab C225 (ATCC accession number HB-8508), or antibodies or antibody fragments having binding specificity thereto.

[0165] Small molecule antagonists of EGFR include gefitinib (Iressa®), razertinib, erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8, and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). In some embodiments, the EGFR inhibitor is one or more of cetuximab, gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Girotrif). Further non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. The EGFR inhibitor may be ERAS-801. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family includes HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4). In some embodiments, the EGFR inhibitor may be bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, ruxolitinib, sunitinib, vemurafenib, abrocitinib, aciminib, futivatinib, ibrutinib, imatinib, pacritinib, or sorafenib. In some embodiments, references to the term EGFR inhibitor include any such EGFR inhibitor disclosed in any one of the following patent applications: WO2023041071, WO2023049312, WO2023020600,WO2023284747, WO2022206797, WO2022258977, WO2022033416, WO2022033410, WO2022105908, WO2022100641, WO2022014639, WO2022007841, WO202 1018009, WO2021057882, WO2021252661, WO2021018003, WO2021073498, WO2021238827, WO2020254547, WO2020216371, WO2020147838, WO202020748 3, WO2020254572, WO2020001350, WO2021001351, WO2019164948, WO2019218958, WO2019046775, WO2019015655, WO2018121758, WO2018218963, WO2 017220007, WO2017205459, WO2017161937, WO2016192609, WO199633980, WO199630347, WO199730034, WO199730044, WO199738994, WO199749688, WO 199802434, WO199738983, WO199519774, WO199519970, WO199713771, WO199802437, WO199802438, WO199732881, WO199833798, WO199732880, WO19 9732880, WO199702266, WO199727199, WO199807726, WO1997 / 34895, WO199631510, WO199814449, WO199814450, WO199814451, WO199509847, WO1997 19065, WO199817662, WO199935146, WO199935132, WO199907701, WO199220642, DE19629652, EP682027, EP837063, EP0787772, EP0520722, EP0566226, CN115960018, CN110283162, CN114044774, CN111973601, CN111973602, and CN113896744, each of these, includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.The entire text is incorporated herein by reference.

[0166] ii) HER2 inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more HER2 inhibitors. The HER2 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the HER2 inhibitor is one or more of tucatinib, rastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), adtrastuzumab emtansine (Kadcyla), and neratinib (Nerlinks). Non-exclusive examples of HER2 inhibitors include monoclonal antibodies, such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa®), erlotinib (Tarceva®), pyritinib, CP-654577, CP-724714, canertinib (CI1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW2992, ARRY-334543, and JNJ-26483327. In some embodiments, references to the term HER2 inhibitor include any such HER2 inhibitor disclosed in any one of the following patent applications: WO2021156178, WO2021156180, WO2021213800, WO2021088987, WO2013561183, and WO2013056108, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0167] iii) MET inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more MET inhibitors. The MET inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the MET inhibitor is one or more of crizotinib (Zalkoli), cabozantinib (Cometriq, Cabometyx), capmatinib (Tabrecta), tepotinib (Tepmetco), savolitinib (Volitinib), onarutuzumab (MetMab), foretinib (GSK1363089), MGCD-265 (Amvatinib), SU11274, and SU5416. In some embodiments, references to the term MET inhibitor include any such MET inhibitor disclosed in any one of the following patent applications: WO2022226168, WO2021222045, WO2020047184, WO2020015744, WO2020244654, WO2020156453, WO2019206268, WO2018077227, WO2017012539, WO2016015653, WO2016012963, WO201201567 7, WO2011162835, WO2010089507, WO2009091374, WO2009056692, WO2008051547, WO2007130468, US2012237524, CN103497177, CN107311983, CN107382968, CN110218191, and TW201331206, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0168] iv) AXL inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more AXL inhibitors. The AXL inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. AXL is a receptor tyrosine kinase belonging to the TAM family of receptors, which also includes TYRO3 and MERTK. In some embodiments, the AXL inhibitor is one or more of vemcentib, BGB324, R428, SGI-7079, TP-0903, BMS-777607, UNC2025, and TP-0903. In some embodiments, references to the term AXL inhibitor include any such AXL inhibitor disclosed in any one of the following patent applications: WO2023045816, WO2022237843, WO2022246179, WO2021012717, WO2021088787, WO2021067772, WO2021239133, WO2021204713, WO2020238802, WO2019 039525, WO2019101178, WO2019074116, WO2017146236, WO2016097918, WO2015012298, WO2010005876, WO2010083465, CN115073367, and JP2022171109, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0169] v) IGFR inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more insulin-like growth factor receptor 1 (IGF-1R) inhibitors. The IGFR inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. IGFR inhibitors have been developed to target the IGFR receptor, which plays a critical role in cancer progression and metastasis. In some embodiments, the IGFR inhibitor is one or more of lincitinib, AXL1717, OSI-906 (lincitinib), BMS-754807, BI836845, AZ12253801, PQIP (pyrrolo[1,2-a]quinoxaline), and NVP-AEW541. In some embodiments, references to the term IGFR inhibitor include any such IGFR inhibitor disclosed in any one of the following patent applications: WO2022115946, WO2022217923, WO2021203861, WO2021246413, WO2020116398, WO2019046600, WO2018195250, WO2018221521 WO2018204872, WO2017072196, WO2016173682, WO2015162291, WO2015162292, WO2010066868, WO2006069202, and CN112125916, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0170] vi) RET inhibitors In some embodiments, the compositions and methods described herein may include compound A combined with a rearranged (RET) inhibitor that is rearranged during one or more transfections. The RET inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. RETs play important roles in various cellular processes, including cell proliferation, differentiation, survival, and migration. RETs are activated by binding to their ligands, such as ligands of the glial cell line-derived neurotrophic factor (GDNF) family, which leads to the activation of downstream signaling pathways that facilitate these cellular processes. In some embodiments, the RET inhibitor is one or more of pralcetinib, serpercatinib (LOXO-292), BLU-667, RXDX-105, TPX-0046, GSK3179106, molydastat (BAY85-3934), and RPI-1 (retrofin). In some embodiments, references to the term RET inhibitor include any such RET inhibitor disclosed in any one of the following patent applications: WO2021211380, WO2021057963, WO2021043209, WO2021222017, WO2020035065, WO2020114487, WO2020200314, WO2020200316, WO2020114494, WO2018071447, WO2018213329, WO2017079140, W O2014050781, CN113943285, CN113683610, CN113683611, CN113620944, CN113620945, CN113527291, CN113527292, CN113527290, CN113135896, CN111057075, CN111233899, and CN111362923, each of these, including the compound structure disclosed in the said document, is specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0171] vii) ROS1 inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more c-ros oncogene 1 (ROS1) inhibitors. The ROS1 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agent described herein. ROS1 is a receptor tyrosine kinase belonging to the insulin receptor family and plays a role in various cellular processes, including cell proliferation, differentiation, survival, and migration. In some embodiments, the ROS1 inhibitor is one or more of taretrectinib, DS-6051b, TPX-0131, GZD824, and PF-06463922. In some embodiments, references to the term ROS1 inhibitor include any such ROS1 inhibitor disclosed in any one of the following patent applications: WO2021098703, WO2020024825, and US2017079972, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0172] viii) PDGFR inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more platelet-derived growth factor receptor (PDGFR) inhibitors. The PDGFR inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. PDGFR is a family of receptor tyrosine kinases consisting of two members, PDGFRα and PDGFRβ. They are activated by binding to their ligands, such as platelet-derived growth factor (PDGF), which leads to the activation of downstream signaling pathways that promote cell growth, proliferation, and survival. In some embodiments, the PDGFR inhibitor is one or more of CP-673451, imatinib, nintedanib (Ofev), sunitinib (Stent), pazopanib (Botrian), regorafenib (Stivarga), and dasatinib (Sprycel).

[0173] ix) FGF inhibitorsIn some embodiments, the compositions and methods described herein may include compound A in combination with a fibroblast growth factor (FGF) inhibitor. The FGF inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agent described herein. FGFR is a family of receptor tyrosine kinases consisting of four members, FGFR1-4. FGFRs are activated by binding to their ligand, fibroblast growth factor (FGF), which leads to the activation of downstream signaling pathways that promote cell proliferation, differentiation, and survival. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR2. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR4. In some embodiments, the FGFR inhibitor is one or more of futivatinib (TAK-659), erdafitinib (Barvasa), infiglatinib (Truseltiq), Debio1347, and logaratinib (BAY1163877). In some embodiments, references to the term FGFR inhibitor include any such FGFR inhibitor disclosed in any one of the following patent applications: WO2022033472, WO2022152274, WO2022166469, WO2022206939, WO2021037219, WO2021089005, WO2021113462, WO2020185532, WO2019213544, WO2020164603, WO2019154364, WO2019034076, WO2019213506, WO2019223766, WO2 018028438, WO2018153373, WO2018121650, WO2018010514, WO2017028816, WO2017118438, WO2016134320, WO2015008844, WO2014172644, WO2014007951, WO2013179033, WO2013087578, WO2012047699, CN105906630, CN115869315, CN115141176, CN115043832, and CN115028634, each of these in whole is incorporated herein by reference. In some embodiments, FGF pathway inhibitors target FGF ligands.Such FGF pathway inhibitors include FGF ligand traps and antibodies. Non-limiting examples include FP-1039, an FGF ligand trap consisting of the extracellular domain of FGFR1 fused to the Fc portion of human IgG1, designed to sequester FGF ligands and inhibit FGF signaling, and MFGR1877S, a monoclonal antibody targeting FGF ligands, designed to block FGF-mediated signaling, including the compound structures disclosed herein, which are incorporated herein by reference.

[0174] x) VEGF inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more vascular endothelial growth factor (VEGF) signaling inhibitors. VEGF (vascular endothelial growth factor) signaling inhibitors are a class of drugs that target signaling pathways mediated by VEGF and its receptors. VEGF plays a crucial role in angiogenesis, the process of forming new blood vessels from existing ones, and is overexpressed in many types of cancer, making it an attractive target for cancer treatment. VEGF inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the VEGF inhibitor is an antibody or antigen-binding domain that specifically binds to VEGF (e.g., bevacizumab), or a soluble VEGF receptor or its ligand-binding domain, e.g., VEGF-TRAP®, and an anti-VEGF receptor agent (e.g., an antibody or antigen-binding domain that specifically binds to it). In some embodiments, the VEGF inhibitor is one or more of bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, and pazopanib.

[0175] e) PI3K / mTOR pathway inhibitors The compositions and methods described herein may include compound A in combination with one or more inhibitors of the PI3K-AKT-TOR signaling pathway. The PI3K-AKT-mTOR signaling pathway is a critical intracellular pathway that controls a wide range of cellular processes, including cell proliferation, growth, metabolism, and survival. This pathway is initiated when growth factors such as insulin or IGF-1 bind to cell surface receptors and activate phosphoinositide 3-kinase (PI3K). The activated PI3K then phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to produce phosphatidylinositol 3,4,5-trisphosphate (PIP3), which then activates AKT. The activated AKT phosphorylates various downstream targets, including the tuberous sclerosis complex (TSC1 / TSC2), to activate mTOR (mammalian target of rapamycin) complex 1 (mTORC1). Activated mTORC1 promotes protein synthesis and cell growth by phosphorylating key regulators of translation initiation, such as S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1).

[0176] i) PI3K inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more PI3K inhibitors. The PI3K inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein.PI3K inhibitors include wartmannin, 17-hydroxywartmannin analog described in WO06 / 044453, 4-[2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)piperazine-1-yl]methyl]thieno[3,2-d]pyrimidine-4-yl]morpholine (also known as pictilisib or GDC-0941, described in WO09 / 036082 and WO09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4 ,5-c]quinoline-1-yl]phenyl]propionitrile (also known as BEZ235 or NVP-BEZ235, described in WO06 / 122806), (S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740), LY294002(2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (Axon (Available from Medchem), PI103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]fl[3,2-d]pyrimidine-2-yl]phenol hydrochloride (Available from Axon Medchem), PIK75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridine-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (Available from Axon Medchem), PIK90 (N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-nicotinamide (Axon This includes, but is not limited to, AS-252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidined-2,4-dione (available from Axon Medchem), TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrinidine-4-one (available from Axon Medchem), XL-765, and XL-147.Other PI3K inhibitors include demethoxypyridine, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, paromide 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136. In some embodiments, the PI3K inhibitor is alpelisib or copanlisib.

[0177] ii) AKT inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more AKT inhibitors. The AKT inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. AKT inhibitors include ipatasertib, GSK-2141795, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem.J.2005,385(Pt.2):399-408), Akt-1-1,2 (inhibits Akl and 2) (Barnett et al., Biochem.J.2005,385(Pt.2):399-408), API-59CJ-Ome (e.g., Jin et al., Br.J.Cancer 2004,91:1808-12), 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05 / 011700), indole-3-carbinol and its derivatives (e.g., U.S. Patent No. 6,656,963, Sarkar and Li J. This includes, but is not limited to, PI3K / AKT inhibitors (Nutr.2004,134(12 Suppl):3493S-3498S), perifosine (e.g., Dasmahapatra et al. Clin. Cancer Res.2004,10(15):5242-52), phosphatidylinositol ether lipid analogs (e.g. Gills and Dennis Expert. Opin. Investig. Drugs 2004,13:787-97), and trisirivine (TCN or API-2 or NCI discriminant: NSC154020; Yang et al., Cancer Res.2004,64:4394-9). PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors listed in Cancers(Basel)2015 Sep;7(3):1758-1784. For example, PI3K / AKT inhibitors may be selected from one or more of the following: NVP-BEZ235, BGT226, XL765 / SAR245409, SF1126, GDC-0980, PI-103, PF-04691502, PKI-587, and GSK2126458.

[0178] iii) mTOR inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more mTOR inhibitors. The mTOR inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. mTOR inhibitors include ATP competitive mTORC1 / mTORC2 inhibitors, e.g., PI-103, PP242, PP30; Torin1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, e.g., temsirolimus (Torisel®); everolimus (Afinitor®, WO94 / 09010); and Ridafo Rolimus (also known as deforolimus or AP23573); rapamycin, e.g., as disclosed in WO98 / 02441 and WO01 / 14387, e.g., AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolite)- Rapamycin (also known as ABT578); 32-deoxorapamycin; 16-pentinyloxy-32(S)-dihydrolapanisin; derivatives disclosed in WO05 / 005434; U.S. Patents Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and WO This includes, but is not limited to, derivatives disclosed in 94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018204416, as well as phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a disteric inhibitor such as RMC-5552 (see e.g., WO2018204416, WO2019212990, and WO2019212991).

[0179] iv) MNK inhibitors In some embodiments, the compositions and methods described herein may comprise compound A in combination with one or more mitogen-activated protein kinase interaction kinase (MNK) inhibitors. The MNK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The MNK protein is activated downstream of the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a crucial role in regulating cell proliferation, differentiation, and survival. MNK phosphorylates eIF4E, a key component of the eukaryotic translation initiation complex that enhances the translation of certain mRNAs, including those encoding proteins involved in cell cycle regulation and oncogenesis. In some embodiments, the MNK inhibitors are one or more tomibocertib (eFT508), CGP57380, and SEL201. In some embodiments, references to the term MNK inhibitor include any such MNK inhibitor disclosed in any one of the following patent applications: WO2021098691, WO2020108619, WO2020086713, WO2018152117, WO2018228275, WO2015200481, and CN115583942, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0180] v) eIF4 inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more eukaryotic initiation factor 4A (eIF4A) inhibitors. The eIF4A inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. eIF4A is a key component of the eukaryotic translation initiation complex and functions as an RNA helicase that unwinds the secondary structure of mRNA and promotes ribosome binding. eIF4A is required for the translation of many cancer-related genes and is an attractive therapeutic target for cancer treatment. In some embodiments, the eIF4A inhibitors are one or more zotatifine (eFT226), silvestrol, patheamine A, and locagrate. In some embodiments, references to the term eIF4A inhibitor include any such eIF4A inhibitor disclosed in any one of the following patent applications: WO2023034813, WO2021195128, and WO2017091585, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0181] In some embodiments, the compositions and methods described herein may comprise one or more eukaryotic initiation factor 4G (eIF4G) inhibitors. The eIF4G inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The eIF4G family comprises several proteins involved in the initiation of protein translation. eIF4G acts as a scaffold for other proteins, including eIF4E and eIF4A, to form the eIF4F complex, which binds to the 5' cap of mRNA and plays a role in unwinding the secondary structure of mRNA to enable ribosome scanning and translation initiation. In some embodiments, the eIF4G inhibitors are one or more patheamine A and hypristanol.

[0182] f) DNA damage response inhibitors The compositions and methods described herein may include compound A in combination with one or more DNA damage response (DDR) inhibitors. The DDR pathway is a vital cellular pathway activated in response to DNA damage, essential for maintaining genomic stability and thereby preventing the development of cancer. However, cancer cells often have defects in the DDR pathway, making them more sensitive to DDR inhibitors. DDR inhibitors have shown promise in preclinical studies as potential cancer therapies, particularly in combination with other drugs.

[0183] i) Wee1 inhibitors In some embodiments, the compositions and methods described herein may comprise compound A in combination with one or more Wee1 inhibitors. Wee1 is a kinase that plays a crucial role in regulating the cell cycle by inhibiting the activity of cyclin-dependent kinases (CDKs) and blocking cell progression through the G2 / M checkpoint. Wee1 is overexpressed in several cancer types and is involved in tumor growth and survival. In some embodiments, the Wee1 inhibitor is one or more of imp7068, adavocertib, or ZNL-02-096. In some embodiments, references to the term Wee1 inhibitor include any such Wee1 inhibitor disclosed in any one of the following patent applications: WO2022011391, WO2022247641, WO2021043152, WO2020221358, WO2020083404, WO2020192581, WO2019085933, WO2018133829, WO2015115355, WO2015183776, WO2014085216, and CN114831993. Each of these includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0184] ii) CHK inhibitors In some embodiments, the compositions and methods described herein may comprise compound A in combination with one or more checkpoint kinase (CHK) inhibitors. The CHK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. CHK1 kinase is a key regulator of the cell cycle and DNA damage response pathways. In some embodiments, the CHK inhibitor is a CHK1 inhibitor. In some embodiments, the CHK inhibitor is a CHK2 inhibitor. In some embodiments, the CHK1 inhibitor is one or more ravellintib, LY2606368, GDC-0575, and MK-8776. In some embodiments, references to the term CHK1 inhibitor include any such CHK1 inhibitor disclosed in any one of the following patent applications: WO2021113661, WO2021104461, WO2019012030, WO2010118390, WO2008067027, WO2002070494, and TW202126818, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0185] iii) ATM inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more ataxia telangiectasia mutation (ATM) inhibitors. The ATM inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. ATMs play a role in regulating the replication stress response and maintaining genomic stability. In some embodiments, the ATM inhibitors are one or more M4076, AZD0156, KU-60019, and VE-821. In some embodiments, references to the term ATM inhibitor include any such ATM inhibitor disclosed in any one of the following patent applications: WO2021197339, WO2021098734, WO2021260580, WO2007026157, WO2006085067, and US2016113935, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0186] iv) ATR inhibitors In some embodiments, the compositions and methods described herein may comprise compound A in combination with one or more ataxia telangiectasia and Rad3-related (ATR) inhibitors. The ATR inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the ATR inhibitors are one or more ceraraerutib, VE-821, RP-350, AZ20, VX-970, abd110, VX-803, and BAY1895344. In some embodiments, references to the term ATR inhibitor include any such ATR inhibitor disclosed in any one of the following patent applications: WO2023016529, WO2022237875, WO2022268025, WO2021012049, WO2021023272, WO2021260579, WO2021228758, WO2019 050889, WO2019154365, WO2019133711, WO2017059357, WO2013049859, WO2007046426, WO2007015632, and CN113797341, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of these documents is incorporated herein by reference.

[0187] v) PARP inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more poly(ADP-ribose) polymerase (PARP) inhibitors. The PARP inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Seventeen members of the PARP (also known as tankirase) family have been identified. PARP enzymes play a crucial role in DNA damage repair, particularly in the repair of single-strand DNA breaks. PARP inhibitors block the activity of PARP enzymes, leading to the accumulation of DNA damage and ultimately cell death. In some embodiments, the PARP inhibitors are one or more olaparib, lucaparib, niraparib, and veliparib (ABT-888).In some embodiments, references to the term PARP inhibitor include any such PARP inhibitor disclosed in any one of the following patent applications: WO2023051812, WO2023051807, WO2023051716, WO2023278592, WO2022228387, WO2022022664, WO2022000946, WO2022222921, WO2021163530, WO2020122034, WO2020239097, WO2020142583, WO2020156577, WO2020098774, WO20201967 12, WO2019200382, WO2018125961, WO2018205938, WO2018192576, WO2018218025, WO2017032289, WO201717 7838, WO2017029601, WO2017088723, WO2016155655, WO2015154630, WO2013097225, WO2012130166, WO201 1006794, WO2009046205, WO2009063244, WO2008084261, WO2007138351, WO2006110816, WO2005053662, WO2 005012524, CN113698356, CN113603647, CN115073544, CN108938634, CN104887680, CN110343088, CN108976236, and CN107629071, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0188] vi) DNA PK inhibitors In some embodiments, the compositions and methods described herein may comprise compound A in combination with one or more DNA-dependent protein kinase (DNA-PK) inhibitors. The DNA-PK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. DNA-dependent protein kinases (DNA-PKs) are serine / threonine protein kinases that play a crucial role in DNA repair and maintaining genomic stability. In some embodiments, the DNA-PK inhibitors are one or more NU7441, AZD7648, VX-984, M3814, and CC-115. In some embodiments, references to the term DNA-PK inhibitor include any such DNA-PK inhibitor disclosed in any one of the following patent applications: WO2022187965, WO2021197159, WO2021260583, WO2021204111, WO2021104277, WO2021098813, WO2021022078, WO2020259613, WO2019143678, WO2019143 675, WO2019201283, WO2015058031, WO2014159690, WO2012028233, WO2009010761, WO2006032869, WO2006109084, CN112574179, CN112300132, and CN112300126, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0189] g) Cell cycle inhibitors The compositions and methods described herein may include compound A in combination with one or more cell cycle inhibitors. Cell cycle inhibitors target specific proteins involved in regulating the cell cycle, the process by which cells divide and replicate their DNA. Non-limiting examples include cyclin-dependent kinases (CDKs), aurora kinases, and polo-like kinases (PLKs). CDKs are a family of kinases involved in regulating the cell cycle. CDK inhibitors block the activity of these kinases, resulting in cell cycle arrest and / or apoptosis. Aurora kinases are a family of serine / threonine kinases that play a crucial role in regulating mitosis. Aurora kinase inhibitors block the activity of these kinases, resulting in mitotic arrest and cell death. PLKs are a family of serine / threonine kinases involved in regulating multiple stages of the cell cycle. PLK inhibitors block the activity of these kinases, resulting in cell cycle arrest and / or apoptosis.

[0190] i) CDK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more CDK inhibitors. The CDK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Cyclin-dependent kinases are a family of protein kinases that regulate cell division and proliferation. Cell cycle progression is controlled by cyclins such as CDK1, CDK2, CDK3, CDK4, and CDK6 and their associated cyclin-dependent kinases, while other CDKs such as CDK7, CDK8, and CDK9 are important for transcription. CDK binding to cyclins forms heterodimeric complexes that phosphorylate their substrates on serine and threonine residues, which then initiate the events necessary for cell cycle transcription and progression. In some embodiments, the CDK inhibitor is a CDK2 inhibitor. In some embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor. In some embodiments, the CDK inhibitor is a CDK7 inhibitor. In some embodiments, the CDK inhibitor is a CDK9 inhibitor. In some embodiments, the CDK inhibitor is one or more palbociclib, ribociclib, abemaciclib, and trilaciclib. In some embodiments, the CDK inhibitor is one or more of tagtocilib (PF-07104091), sericiclib, borcilib P1446A-05, BLU-222, dynacilib, AT-7519, RGB286638, and AZD4573.

[0191] In some embodiments, references to the term CDK inhibitor include any such CDK inhibitor disclosed in any one of the following patent applications: WO2022166793, WO2022187611, WO2022130304, WO2021227906, WO2021057867, WO2020207260, WO2020138370, WO2020125513, WO2020148635, WO2020215156, WO2020052627, WO2017177837, WO2017162215, WO2017177836, WO2016193939, WO2016 014904, WO2016015598, WO2016015605, WO2015181737, WO2012061156A1, WO2012038411, WO2010020675, WO2010125004, WO2007139732, WO2006024945, CN114478529, CN108794496, CN105294737, CN107652284, KR20180106188, and US2017152269, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0192] ii) Aurora kinase inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more aurora kinase inhibitors. The aurora kinase inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Aurora kinases are a family of serine / threonine kinases that play a vital role in regulating cell division and maintaining genomic stability. The aurora kinase family consists of three members: aurora A, aurora B, and aurora C. In some embodiments, the aurora kinase inhibitor is one or more palbociclib, ribociclib, and abemaciclib. In some embodiments, the aurora kinase inhibitor is one or more of aricertib, danucertib, valacertib, and MLN8237. In some embodiments, references to the term aurora kinase inhibitor include any such aurora kinase inhibitor disclosed in any one of the following patent applications: WO2021110009, WO2021008338, WO2020112514, WO2019129234, WO2016077161, WO2013143466, WO2011103089, WO2010081881, WO2010133794 WO2009134658, WO2008001886, WO2007095124, WO2007003596, WO2006129064, CN114276227, CN108078991, CN106543155, CN104211692, and CN104098551, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0193] iii) PLK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more polo-like kinase (PLK) inhibitors. The PLK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. PLKs are a family of serine / threonine kinases that play a vital role in regulating cell division, DNA damage response, and mitotic progression, and consist of four members: PLK1, PLK2, PLK3, and PLK4. In some embodiments, the PLK inhibitors are one or more of borasertib, onvansertib, BI2536, and GSK461364. In some embodiments, references to the term PLK inhibitor include any such PLK inhibitor disclosed in any one of the following patent applications: WO2011012534A1, WO2010065134, WO2009130453, WO2009042806, WO2004043936, WO2007030361, WO2006021547, CN115804777, and EP2325185, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0194] iv) Kinesin superfamily inhibitors of microtubule motor proteins In some embodiments, the compositions and methods described herein may include compound A in combination with one or more kinesin spindle protein (KSP) inhibitors. In some embodiments, the compositions described herein may include one or more kinesin family (KIF) inhibitors. In some embodiments, the KSP inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agent described herein. KSP and KIF are subsets of the kinesin superfamily of microtubule motor proteins. KSP, also known as Eg5, is a member of the kinesin superfamily of motor proteins that play a crucial role in mitotic spindle formation and cell division. KSP inhibitors selectively target rapidly dividing cancer cells by disrupting spindle formation and inducing mitotic arrest. In some embodiments, the KSP inhibitor is one or more of SB743921, monastrole, S-trityl-L-cysteine ​​(STLC), and filanesib (ARRY-520). In some embodiments, the KIF inhibitor is an inhibitor of kinesin 8 family microtubule motor proteins. In some embodiments, the kinesin-8 family protein is KIF18A. In some embodiments, the KIF inhibitor is one or more of AMG650, BTB-1, K03861, and SJ000291942.In some embodiments, references to the term microtubule motor protein kinesin superfamily inhibitors include any such microtubule motor protein kinesin superfamily inhibitors disclosed in any one of the following patent applications: WO2015114854, WO2015114855, WO2010084186, WO2006101761, WO2006110390, WO2006044825, WO2006078574, WO2005060654, WO2004092147, WO20 04037171, WO2004058700, WO2003050064, WO2003105855, WO2022037665, WO2018114804, WO2017162663, WO2016207089, WO2012073375, JP2014162787, JP2019189590, JP2013166713, and KR20220145566, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0195] v) DYRK1 inhibitors In some embodiments, the compositions and methods described herein may comprise compound A in combination with one or more bispecific tyrosine phosphorylation-regulated kinase 1 (DYRK1) inhibitors. The DYRK1 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. DYRK1 is a member of the DYRK (bispecific tyrosine phosphorylation-regulated kinase) family of protein kinases. It plays an essential role in various cellular processes, including cell cycle regulation, neuronal development, and transcriptional regulation. In some embodiments, the DYRK1 inhibitor is one or more of harmine, INDY, D4476, and AZ191. In some embodiments, references to the term DYRK1 inhibitor include any such DYRK1 inhibitor disclosed in any one of the following patent applications: WO2023277331A1, WO2023140846A1, WO2017181087A1, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0196] h) Anti-apoptotic protein inhibitors The compositions and methods described herein may comprise compound A in combination with one or more anti-apoptotic protein inhibitors. In some embodiments, the anti-apoptotic protein inhibitor may be administered or formulated in combination with compound A described herein and / or any additional therapeutic agent. Anti-apoptotic inhibitors target proteins that play a role in blocking apoptosis, a form of programmed cell death. Apoptosis is a key mechanism for eliminating damaged or unwanted cells. Anti-apoptotic proteins are a family of proteins that inhibit the apoptotic pathway and thereby prevent cell death. There are several known classes of anti-apoptotic inhibitors, including Bcl-2 inhibitors, XIAP inhibitors, survivin inhibitors, Mcl-1 inhibitors, and FLIP inhibitors. These inhibitors act by binding to specific anti-apoptotic proteins and inhibiting their activity, thereby promoting cell death in cancer cells. In some embodiments, the compositions described herein may comprise one or more anti-apoptotic protein inhibitors. The anti-apoptotic protein inhibitor may be administered or formulated in combination with the RAS(ON) inhibitor described herein and / or any additional therapeutic agent. In some embodiments, the anti-apoptotic protein inhibitor comprises an MCL-1 inhibitor. Non-exclusive examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845. The myeloid cell leukemia-1 (MCL-1) protein is one of the major anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. MCL-1 overexpression is closely associated with tumor progression and resistance to targeted therapies, including BCL-2 inhibitors such as ABT-263, as well as to conventional chemotherapy. In some embodiments, anti-apoptotic protein inhibitors include BCL protein inhibitors. Examples of BCL protein inhibitors include, but are not limited to, venetoclax (Veneclexta), navitoclax (ABT-263), A-1331852, S63845, and AT-101.

[0197] i) Autophagy inhibitors The compositions and methods described herein may include compound A in combination with one or more autophagy inhibitors. In some embodiments, the autophagy inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil®), spautin-1, SAR405, bafilomycin A1, 5-amino-4-imidazole carboxamidriboside (AICAR), okadaic acid, autophagy-suppressing algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNAs that inhibit the expression of proteins, including but not limited to ATG5 (which is involved in autophagy), may also be used. In some embodiments, one or more additional therapies include autophagy inhibitors.

[0198] a) ULK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more Unc-51-like kinase (ULK) inhibitors. The ULK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agent described herein. In some embodiments, the ULK inhibitor is a ULK1 / 2 inhibitor. In some embodiments, the ULK inhibitor is one or more of ULK-101, MRT68921, SBI-0206965, MRT67307, MRT68920, MRT68922, MRT199665, LY3009120, and dolsomorphine.

[0199] b) VPS inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more vacuolar protein sorting protein (VPS) inhibitors. The VPS inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. VPS proteins are a family of proteins that play a crucial role in the autophagy process by regulating the formation and function of autophagosomes, which are structures that entangle cellular elements and transport them to lysosomes for degradation. Dysregulation of VPS proteins is associated with a variety of diseases, including cancer, neurodegenerative diseases, and infections. In some embodiments, the VPS inhibitor is a VPS34 inhibitor. In some embodiments, the VPS inhibitor is one or more of PIK-III, VPS34-IN1, SAR405, Spautin-1, and NSC185058.

[0200] c) Macropinocytosis inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more macropinocytosis inhibitors. The macropinocytosis inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. The macropinocytosis inhibitors are compounds that can block or reduce the process of macropinocytosis. In some embodiments, the macropinocytosis inhibitors are one or more of EIPA (ethyl isopropyl amiloride), wartmannin, amiloride, apirimod, Dyngo-4a, and latruncrin B.

[0201] j) WNT / β-catenin pathway inhibitors The compositions and methods described herein may include compound A in combination with one or more WNT / beta-catenin pathway inhibitors. In some embodiments, the WNT / beta-catenin pathway inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The WNT / beta-catenin pathway is a critical signaling pathway that plays a vital role in development, tissue homeostasis, and disease. Dysregulation of this pathway is involved in various cancers and has become an attractive target for cancer treatment. WNT / beta-catenin pathway inhibitors target various components of the pathway, including WNT ligands, receptors, and downstream effectors.

[0202] i) β-catenin inhibitors In some embodiments, the compositions and methods described herein may comprise compound A and one or more β-catenin inhibitors. The β-catenin inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Beta-catenin is a protein that plays a crucial role in the WNT signaling pathway, which regulates various cellular processes, including cell proliferation, differentiation, and migration. In normal cells, β-catenin levels are tightly regulated by a disruption complex that marks β-catenin for degradation. However, in many cancer cells, the disruption complex is impaired, leading to the accumulation of β-catenin in the nucleus and the activation of target genes involved in tumor growth and metastasis.In some embodiments, the WNT / β-catenin inhibitors are FOG-001, OMP-131R10, Foxy-5, LGK974, RXC004, ETC-159, OMP-54F28, niclosamide, OMP-18R5, OTSA-101, BNC101, DKN-01, sulindac, pyrvinium, E7449, BC2059, PRI-724, SM08502, IWP1, IWP2, IWP3, IWP4, IWP12, IWPL6, C59, GNF-6231, GNF-1331, DK-520, DK-419, IgG-2919, Fz7-21, RHPD-P1, SRI37892, 1094-0205, 2124-0331, 3235-0367, NSC36784, NSC654259, IgG-2919, sarinomycin, BMD4702, 3289-8625, J01-017a, FJ9, KY-02061, KY-02327, NSC668036, Petit Pen-N3, SSTC3, CCT03137 4, TCS183, XAV939, AZ1366, G007-LK, MSC2504877, G244-LM, IWR-1, JW74, JW55, K-756, NVP-TNKS656, One or more of the following: MN-64, RK-287107, WIKI4, KY1220, KYA1797K, MSAB, PKF115-584, CGP049090, AV-65, PNU-74654, Windolfen, IQ-1 Tegavivant, Fossenvivant, PNPB-29, ZW4864, SAH-BCL9, Carnosic Acid, xStAx-VHL, NRX-252114, Septuximab Vedotin, PF-06647020, LGR5-mc-vc-PAB-MMAE, LGR5-NMS818, CWP232291, PRI-724 (also known as ICG-001), C-82, and BC2059. In some embodiments, references to the term β-catenin inhibitor include any such β-catenin inhibitor disclosed in any one of the following patent applications: CN104388427 and CN103830211, each of which includes the compound structure disclosed in said document, which is specifically incorporated herein by reference.

[0203] ii) PORCN inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more porcupine (PORCN) inhibitors. The PORCN inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. PORCN is a membrane-bound O-acyltransferase enzyme that plays a crucial role in the WNT signaling pathway by mediating the palmitoylation of WNT ligands. This palmitoylation is essential for the secretion and signaling activity of WNT proteins. Inhibition of PORCN results in a reduction of WNT signaling activity. In some embodiments, the PORCN inhibitor is one or more of LGK974 (WNT974), ETC-1922159, CGX1321, and CWP232291.

[0204] iii) GSK3 inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more glycogen synthase kinase (GSK3) inhibitors. The GSK3 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The GSK3 family consists of two closely related serine / threonine kinases: GSK3α and GSK3β. These kinases are involved in numerous cellular processes, including glycogen metabolism, cell cycle regulation, and Wnt signaling. GSK inhibitors have been studied as potential therapeutic agents for a variety of diseases, including cancer, diabetes, Alzheimer's disease, and bipolar disorder. In some embodiments, the GSK3 inhibitor is one or more of tidoglucib, radubiglucib, LiCl (lithium chloride), CHIR99021, SB216763, AZD1080, and LY2090314. In some embodiments, references to the term GSK3 inhibitor include any such GSK3 inhibitor disclosed in any one of the following patent applications: WO2017153834, WO2014059383, WO2010012398, WO2009017455, WO2003037891, CN107151235, and CN102258783, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0205] iv) CLK inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more Cdc2-like kinase (CLK) inhibitors. The CLK inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. LK (Cdc2-like kinases) is a family of serine / threonine kinases that play a crucial role in regulating premRNA splicing, particularly alternative splicing. There are four members of the CLK family: CLK1, CLK2, CLK3, and CLK4. The CLK family of kinases has been shown to be involved in several diseases, including cancer, neurodegenerative diseases, and viral infections. In some embodiments, the CLK inhibitor is a CLK2 inhibitor. In some embodiments, the CLK2 inhibitor is one or more of lorecivivint, SM08502, SM04690, TG003, KH-CB19, Cmpd-1, T3.5, and CX-4945. In some embodiments, references to the term CLK inhibitor include any such CLK inhibitor disclosed in WO2020006115, which includes the compound structures disclosed in that document, which are specifically incorporated herein by reference.

[0206] k) JAK / STAT pathway inhibitors The compositions and methods described herein may include compound A in combination with one or more JAK / STAT pathway inhibitors. In some embodiments, the JAK / STAT pathway inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agent described herein. The Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway is a signaling pathway involved in many cellular processes, including immune responses, cell proliferation, and differentiation. Dysregulation of this pathway is associated with a variety of diseases, including inflammatory disorders, cancer, and autoimmune diseases. Inhibitors of the JAK / STAT pathway can be used to treat these diseases. In some embodiments, the JAK / STAT pathway inhibitor is an inhibitor of JAK1, JAK2, and / or JAK3. In some embodiments, the JAK inhibitor is one or more of the following: ruxolitinib (Jakafi®), pacritinib, fedratinib, tofacitinib (Xeljanz®), abrocitinib, filgotinib, oclacitinib, peficitinib, upadacitinib, deuclavacitinib, delgocitinib, and baricitinib (Olumiant®).In some embodiments, references to the term JAK inhibitor include any such JAK inhibitor disclosed in any one of the following patent applications: WO2023011301, WO2023201044, WO2022143629, WO2022251434, WO2022067106, WO2022033551, WO2021244323, WO2021238817, WO2021238818, WO2021178991, WO2021136345, WO2021190647, WO2020219639, WO2020182 159, WO2020155931, WO2020038457, WO2020219524, WO2020173400, WO2018204233, WO2018204238, WO2018169875, WO2018117152, WO2017215630, WO2016070697, WO2016027195, CN117815195, CN117815367, and CN115969796, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0207] In some embodiments, the JAK / STAT inhibitor is a STAT inhibitor. In some embodiments, the STAT inhibitor is an inhibitor of STAT3 and / or STAT5. In some embodiments, the STAT inhibitor is a STAT3 degrader. In some embodiments, the STAT inhibitor is one or more of TTI-101, C-188-9, WP1066, VVD-130850, LLL12B, STA-21, SD-36, Stattic, S3I-201, OPB-31121, or napabucasin (BBI608). In some embodiments, references to the term STAT inhibitor include any such STAT inhibitor disclosed in any one of the following patent applications: WO2024030628, WO2023164680, WO2023192960, WO2023133336, WO2020206424, WO2023107706, WO2021150543, WO2008151037, and CN109288845, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0208] l) Epigenetic modifiers The compositions and methods described herein may include compound A in combination with one or more epigenetic modulators. Epigenetic modulators are a class of therapeutic agents that target enzymes that modify the structure and function of chromatin, the complex of DNA and proteins that make up chromosomes. These enzymes, including histone deacetylase (HDAC), histone methyltransferase (HMT), and DNA methyltransferase (DNMT), play a crucial role in gene expression and regulation by modifying DNA packaging and influencing how DNA is read and transcribed. Epigenetic modulators act by altering the activity of these enzymes, either by inhibiting or enhancing their function, in order to regulate gene expression in a specific manner. By targeting specific epigenetic modifications such as acetylation, methylation, and DNA methylation, these therapies have the potential to treat a wide range of diseases, including cancer, inflammatory diseases, and neurological disorders.

[0209] i) HDAC inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more histone deacetylase (HDAC) inhibitors. The HDAC inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. There are several classes of HDACs, including class I, class IIa, class IIb, class III, and class IV. Class I HDACs are further divided into HDAC1, HDAC2, HDAC3, and HDAC8, and class IIa HDACs include HDAC4, HDAC5, HDAC7, and HDAC9. Class IIb HDACs consist of HDAC6 and HDAC10, and class III HDACs are known as sirtuins. HDAC inhibitors can target various classes of HDACs, and their specific effects on gene expression can vary depending on the HDAC they target. In some embodiments, the HDAC inhibitor is one or more of the following: vorinostat (Zolinza), romidepsin (Istodax), bellinostat (Beleodax), panobinostat (Faridac), entinostat (MS-275), valproic acid (Depakene), trichostatin A (TSA), sodium butyrate, and mosetinostat (MGCD0103). Non-limiting examples of HDAC inhibitors include trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH589, romidepsin, ACY-1215, and panobinostat. In some embodiments, references to the term HDAC inhibitor include any such HDAC inhibitor disclosed in any one of the following patent applications: WO2022110958, WO2021252628, WO2019204550, WO2018178060, WO2016126724, WO2014143666, WO2013041480, and WO2006120456, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0210] ii) BET inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more bromodomain and extraterminal protein (BET) inhibitors. The BET inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. BET (bromodomain and extraterminal) proteins are a family of epigenetic leader proteins that recognize and bind to acetylated lysine residues on histones, resulting in chromatin remodeling and gene expression regulation. Humans have four BET proteins: BRD2, BRD3, BRD4, and BRDT. BET inhibitors specifically target the bromodomain of BET proteins, inhibiting their binding to acetylated lysine residues on histones and resulting in altered gene expression. BET inhibitors are useful in treating cancer and other diseases characterized by dysregulation of gene expression. In some embodiments, the BET inhibitor is one or more of JQ1, I-BET762, OTX015, RVX-208, and CPI-0610. In some embodiments, references to the term BET inhibitor include any such BET inhibitor disclosed in any one of the following patent applications: WO2022046682, WO2022182857, WO2021107657, WO2021107656, WO2020221006, WO2020053660, WO2018097977, WO2017222977, WO2017142881, WO2015075665, WO2015011084, and CN113264930, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0211] iii) EZH2 inhibitors In some embodiments, the compositions and methods described herein may include compound A combined with one or more Zeste homolog enhancer 2 (EZH2) inhibitors. The EZH2 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. EZH2 is a histone-lysine N-methyltransferase that is a member of the Polycomb repression complex 2 (PRC2) family. EZH2 plays a crucial role in gene expression regulation, particularly by catalyzing histone H3 trimethylation with lysine 27 (H3K27me3), resulting in transcriptional repression of target genes. EZH2 has been found to be overexpressed in several types of cancer and is associated with tumor progression and poor prognosis. In some embodiments, the EZH2 inhibitor is one or more of tazemetostat, GSK2816126, and CPI-1205 (lirametostat). In some embodiments, references to the term EZH2 inhibitor include any such EZH2 inhibitor disclosed in any one of the following patent applications: WO2023030299, WO2022179584, WO2020224607, WO2021243060, WO2021086069, WO2019206155, WO2018133795, WO201 8137639, WO2017184999, WO2017218953, WO2016201328, WO2015195848, WO2013155317, WO2013138361, and CN114621191, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of these documents is incorporated herein by reference.

[0212] iv) Co-REST inhibitors In some embodiments, the compositions and methods described herein may include compound A in combination with one or more Co-REST inhibitors. The Co-REST inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Co-REST is a transcriptional co-repressor protein that interacts with various transcription factors to regulate gene expression. Co-REST acts by recruiting histone deacetylase (HDAC) to chromatin, resulting in the repression of gene expression. Inhibition of Co-REST has been proposed as a potential therapeutic strategy for the treatment of various diseases, including neurodegenerative diseases and cancer. In some embodiments, the co-REST inhibitor is one or more of nocodazole, NSC1892, and anacardoic acid.

[0213] v) EP300 In some embodiments, the compositions and methods described herein may include compound A in combination with one or more E1A-binding protein p300 (EP300) inhibitors. The EP300 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. EP300 is a transcriptional coactivator involved in regulating numerous cellular processes, including chromatin remodeling, DNA damage response, and cell cycle progression. EP300 functions as a histone acetyltransferase, catalyzing the transfer of acetyl groups to lysine residues on histone proteins, resulting in changes in chromatin structure and gene expression. EP300 activity is involved in diseases such as cancer, cardiovascular disease, and neurological disorders. In some embodiments, the EP300 inhibitor is one or more of C646, A-485, NU9056, and L002. In some embodiments, references to the term EP300 inhibitor include any such EP300 inhibitor disclosed in any one of the following patent applications: WO2021213521 and WO2016044694, each of which includes the compound structure disclosed in said document, which is specifically incorporated herein by reference.

[0214] vi)LSD1 In some embodiments, the compositions and methods described herein may include compound A in combination with one or more lysine-specific demethylase 1 (LSD1) inhibitors. The LSD1 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. LSD1 is an enzyme that plays a crucial role in regulating gene expression through histone modification. It specifically removes a methyl group from lysine 4 on histone 3, resulting in gene repression. Dysregulation of LSD1 is associated with a variety of diseases, including cancer and neurodegenerative disorders. In some embodiments, the LSD1 inhibitor is one or more of GSK2879552, IMG-7289, ORY-1001, IMG-8419, SP-2577, CC-90011, HCI-2509, and INCB059872. In some embodiments, references to the term LSD1 inhibitor include any such LSD1 inhibitor disclosed in any one of the following patent applications: WO2021095840, WO2021175079, WO2021058024, WO2020047198, WO2020052649, WO2020015745, WO2020052647, W O2018137644, WO2017184934, WO2017027678, WO2017116558, WO2017149463, WO2016161282, WO2015123465, WO2015123424, WO2013057322, WO2013057320, WO2012135113, CN114805261, CN111072610, CN107174584, CN110478352, CN106432248, and CN106045881, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0215] vii)PRMT5 In some embodiments, the compositions and methods described herein may include compound A in combination with one or more protein arginine methyltransferase 5 (PRMT5) inhibitors. The PRMT5 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. PRMT5 is a member of the PRMT family that catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the nitrogen atom of an arginine residue in a target protein. PRMT5 is involved in a variety of biological processes, including gene expression regulation, signal transduction, and DNA repair. In some embodiments, the PRMT5 inhibitor is one or more of TNG908, TNG462, AMG193, GSK591, EPZ015666, TC-E 5003, and MS023. In some embodiments, references to the term PRMT5 inhibitor include any such PRMT5 inhibitor disclosed in any one of the following patent applications: WO2023001133, WO2022206964, WO2022153161, WO2021068953, WO2021088992, WO2020259478, WO2020205660, WO2020250123, WO2020033288, WO2019102494, WO2019112719, WO2019 180631, WO2018065365, WO2017153186, WO2017212385, WO2017032840, WO2016022605, WO2014100695, WO2014145214, WO2014100719, CN111825656, CN114558014, CN11304554, and CN112778275, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0216] viii)MAT2A In some embodiments, the compositions and methods described herein may include compound A in combination with one or more methionine adenosyltransferase 2A (MAT2A) inhibitors. The MAT2A inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. MAT2A is an enzyme that catalyzes the production of S-adenosylmethionine (SAM), a key cofactor in many biological processes, including DNA methylation, protein methylation, and polyamine synthesis. Elevated MAT2A expression has been associated with various cancers. In some embodiments, the MAT2A inhibitors are one or more of cycloleucine and 2-hydroxy-4-methylthiobutanoic acid. In some embodiments, references to the term MAT2A inhibitor include any such MAT2A inhibitor disclosed in any one of the following patent applications: WO2022256808, WO2022256806, WO2019191470, and CN115716831, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0217] ix) DOT1L In some embodiments, the compositions and methods described herein may include compound A in combination with one or more telomere silencing disruptor 1-like (DOT1L) inhibitors. The DOT1L inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. DOT1L is a histone methyltransferase enzyme that catalyzes the methylation of lysine 79 on histone H3. This modification is related to transcriptional elongation and is important for maintaining gene expression programs. The DOT1L family includes enzymes involved in epigenetic regulation and transcriptional control, and their dysregulation is associated with a variety of diseases, including cancer. In some embodiments, the DOT1L inhibitor is one or more of EPZ-5676 (pinometostat) and EPZ-004777. In some embodiments, references to the term DOT1L inhibitor include any such DOT1L inhibitor disclosed in any one of the following patent applications: WO2016090271, WO2014100662, and CN108997480, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0218] iix)UBA1 In some embodiments, the compositions and methods described herein may include compound A in combination with one or more ubiquitin-activating enzyme inhibitors (e.g., UBA1 inhibitors). The UBA1 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. UBA1, also known as ubiquitin-activating enzyme 1, is a key enzyme involved in the ubiquitination process, a fundamental cellular mechanism for proteolysis and regulation. Ubiquitination involves the covalent binding of ubiquitin molecules to target proteins, their marking for degradation by the proteasome, or the regulation of their activity, localization, or interactions within cells. Several inhibitors have been developed to modulate UBA1 activity with the aim of disrupting ubiquitination-mediated processes in diseased cells. These inhibitors typically include, but are not limited to, adenosine-based inhibitors (e.g., PYR-41 and MLN7243) that compete with ATP for binding to the active site of UBA1, thereby inhibiting ubiquitin activation; covalent inhibitors (e.g., TAK-243 (formerly MLN4924)) that form irreversible bonds with specific amino acid residues of the active site of UBA1, resulting in inhibition of its activity; allosteric inhibitors (e.g., compound 2i) that bind to a site on UBA1 different from the active site and induce conformational changes that inhibit its catalytic activity; and fragment-based inhibitors designed based on smaller molecular fragments that bind to UBA1. In some embodiments, the UBA1 inhibitor is one or more of PYR-41, MLN7243, and TAK-243. In some embodiments, references to the term UBA1 inhibitor include any such UBA1 inhibitor disclosed in any one of the following patent applications: WO2016069393A1, WO2016069392A1, and JP2013237627A2, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0219] m) Additional therapeutic agents useful in combination therapy In some embodiments, the compositions and methods described herein may include compound A in combination with one or more farnesyltransferase inhibitors. The farnesyltransferase inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Farnesyltransferase inhibitors (FTIs) are a class of drugs that target the farnesyltransferase enzyme, which plays a role in a process called protein prenylation. Protein prenylation is a critical step in the process of activating certain proteins involved in signaling, cell proliferation, and differentiation. In some embodiments, the farnesyltransferase inhibitor is one or more of tipifarnib, ronafarnib, and lilapradib. In some embodiments, references to the term farnesyltransferase inhibitor include any such farnesyltransferase inhibitor disclosed in any one of the following patent applications: WO2010057028, WO2007042465, WO200136395, WO200064891, WO200042849, WO199938862, WO199928315, WO199829390, WO199426723, CN107312000, CN107365310, KR100375421, KR100388790, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0220] In some embodiments, the compositions and methods described herein may include compound A in combination with one or more casein inhibitors. In some embodiments, the casein inhibitor is SR-3029, a potent ATP-competitive CK1δ and CK1ε inhibitor.

[0221] In some embodiments, the compositions and methods described herein may include one or more FLT3 inhibitors in combination with compound A disclosed herein. FLT3 (Fms-like tyrosine kinase 3), also known as CD135, is a receptor tyrosine kinase (RTK) that plays a crucial role in regulating hematopoiesis, the process by which blood cells are formed. It is primarily expressed on hematopoietic stem cells (HSCs) and progenitor cells in the bone marrow and controls cell proliferation, survival, and differentiation. In some embodiments, FLT3 inhibitors include, but are not limited to, midostaurin, gilteritinib, sorafenib, quizartinib, crenolanib, ponatinib, and quizartinib.

[0222] In some embodiments, the compositions and methods described herein may include compound A in combination with one or more TGFβ pathway inhibitors. In some embodiments, the compositions and methods described herein may include one or more TGFβ inhibitors. The TGFβ inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agent described herein. TGFβ (transforming growth factor beta) is a multifunctional cytokine involved in various cellular processes, including cell proliferation, differentiation, apoptosis, and immune responses. Dysregulation of the TGFβ signaling pathway is associated with various diseases, including cancer, fibrosis, and autoimmune diseases. In some embodiments, the TGFβ inhibitor is one or more of garnicerutib (LY2157299) and bactocerutib (TEW-7197). In some embodiments, the TGFβ inhibitor is one or more of garnicerutib, LY2157299, fresolimmab, reldelimumab, travedersen, curcumin, resveratrol, and small interfering RNAs (siRNAs) for silencing TGFβ receptor expression. In some embodiments, references to the term TGFβ inhibitor include any such TGFβ inhibitor disclosed in any one of the following patent applications: WO2023043473, WO2020104648, WO2020128850, WO2016140884, WO2007018818, WO2004024159, WO200226935, WO2002062753, WO2002062776, and JP2012087076, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0223] In some embodiments, the compositions and methods described herein may include compound A in combination with one or more HSP90 inhibitors. The HSP90 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. HSP90, also known as heat shock protein 90, is a molecular chaperone that plays a crucial role in regulating the folding, stability, and activity of numerous client proteins involved in various cellular processes, including cell cycle progression, signaling, and apoptosis. In some embodiments, the HSP90 inhibitor is one or more of the following: geldanamycin or its derivatives (e.g., 17-AAG, 17-DMAG), KOS 953, radicicol or its derivatives (e.g., PU-H71), SNX-2112, ganetespib, AT13387, onarespib, luminespib, and KW-2478. In some embodiments, references to the term HSP90 inhibitor include any such HSP90 inhibitor disclosed in any one of the following patent applications: WO2021137665, WO2018200534, WO2017151425, WO2015200514, WO2013053833, WO2013009657, WO2013119985, WO2012138894, WO2011044394, WO2009097578, WO2008115719, CN105237533, and CN104030904, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0224] In some embodiments, the compositions and methods described herein may comprise compound A in combination with one or more glutathione peroxidase 4 (GPX4) inhibitors. The GPX4 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. GPX4 is an antioxidant enzyme that plays a crucial role in protecting cells from oxidative stress-induced cell death. GPX4 catalyzes the reduction of lipid hydroperoxides to their corresponding alcohols and functions as a regulator of ferroptosis, a form of regulated cell death driven by lipid peroxide formation. In some embodiments, the GPX4 inhibitor is one or more of RSL3, ML162, DPI7, FINO2, MCB-613, CBS9106, ML210, ODSH, and TLN232. In some embodiments, references to the term GPX4 inhibitor include any such GPX4 inhibitor disclosed in any one of the following patent applications: WO2021132592, US2021244715, and KR20220115536, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0225] In some embodiments, the compositions and methods described herein may include compound A in combination with one or more NRF2 inhibitors. The NRF2 inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. NRF2 is a transcription factor that modulates the expression of genes involved in cellular antioxidant responses, detoxification, and other cytoprotective pathways. It plays a crucial role in cellular defense mechanisms against oxidative stress and other forms of cellular damage. In some embodiments, the NRF2 inhibitor is one or more of ML385, brusatol, CDDO-Im, RTA-408, and trigonelline. In some embodiments, references to the term NRF2 inhibitor include any such NRF2 inhibitor disclosed in any one of the following patent applications: WO2023051088, WO2021202720, KR2022013610, and CN107519168, each of which includes the compound structures disclosed in such documents, each of which is specifically incorporated herein by reference.

[0226] In some embodiments, the compositions and methods described herein may include compound A in combination with one or more TEA domain (TEAD) inhibitors. The TEAD inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. TEAD is a family of transcription factors that play a crucial role in regulating gene expression during embryonic development and tissue homeostasis. The four members of the TEAD family (TEAD1-4) are transcriptional co-activators that bind to DNA via their conserved TEA domains and interact with other transcription factors to activate the expression of target genes. In some embodiments, the TEAD inhibitor is one or more of VT-107, pan-TEAD, VT-104, verteporfin, CA3, IAG933, K-975, IK-595, and statins (see, for example, Chapeau, Emilie and Schmelzle, Tobias (2023) IAG933, an oral selective YAP1-TAZ / pan-TEAD protein-protein interaction inhibitor (PPIi) with pre-clinical activity in monotherapy and combinations with MAPK inhibitors. Nature Cancer). In some embodiments, references to the term TEAD inhibitor include any such TEAD inhibitor disclosed in any one of the following patent applications: WO2023280254, WO2023031781, WO2022258040, WO2020070181, WO2018185266, and WO2017064277, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0227] In some embodiments, the compositions and methods described herein may include compound A in combination with one or more NOTCH / gamma-secretase inhibitors. The NOTCH / gamma-secretase inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the NOTCH / gamma-secretase inhibitor is nilogacestat. In some embodiments, references to the term NOTCH / gamma-secretase inhibitor include any such NOTCH / gamma-secretase inhibitor disclosed in any one of the following patent applications: WO2020208572, WO2017200969, WO2014047390, WO2014047372, WO2011041336, WO2010090954, WO2009008980, WO2009087130, WO2007110335, CN103664904, CN105560244, and KR20200077480, each of which includes the compound structures disclosed in those documents, which are specifically incorporated herein by reference.

[0228] In some embodiments, the compositions and methods described herein may include Compound A in combination with one or more Hedgehog inhibitors. The Hedgehog inhibitors may be administered or formulated in combination with Compound A and / or any additional therapeutic agent described herein. The Hedgehog (Hh) family of proteins are secreted signaling molecules that play important roles in embryonic development and tissue homeostasis in adults. The Hh signaling pathway is involved in regulating cell growth, differentiation, and survival. In some embodiments, the Hedgehog inhibitor is one or more of vismodegib (Erivedge), sonidegib (Odomzo), and glasdegib (Daurismo). In some embodiments, reference to the term Hedgehog inhibitor includes any such Hedgehog inhibitor disclosed in any one of the following patent applications: WO2011063309, and CN107163028, each of which is specifically incorporated herein by reference in its entirety, including the compound structures disclosed in said document.

[0229] The compositions and methods described herein may include Compound A in combination with one or more NFkB pathway inhibitors. The NFkB inhibitors may be administered or formulated in combination with Compound A and / or any additional therapeutic agent described herein. Nuclear factor kappa B (NFκB) is a family of transcription factors involved in regulating various cellular processes including inflammation, immunity, cell survival, and proliferation. Non-limiting examples of NFkB inhibitors include bortezomib (Velcade), curcumin, parthenolide, IKK inhibitors (e.g., IKK-16, BAY11-7082), resveratrol, andrographolide, and proteasome inhibitors (e.g., MG132, lactacystin).

[0230] In some embodiments, the additional therapy is the administration of a side effect limiting agent (e.g., an agent intended to reduce the occurrence or severity of side effects of the treatment). For example, in some embodiments, Compound A can also be used in combination with a therapeutic agent that treats nausea. Examples of agents that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0231] In some embodiments, one or more additional therapies include non-drug therapies (e.g., surgery or radiation therapy). In some embodiments, one or more additional therapies include therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, one or more additional therapies include non-drug therapies (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors).

[0232] Examples of non-drug therapies include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and T cell adoptive transfer (ACT) therapy.

[0233] In some embodiments, Compound A can be used as adjuvant therapy after surgery. In some embodiments, Compound A can be used as neoadjuvant therapy before surgery.

[0234] Radiotherapy may be used in subjects (e.g., mammals (e.g., humans)) to inhibit abnormal cell proliferation or to treat hyperproliferative disorders such as cancer. Techniques for administering radiotherapy are known in the art. Radiotherapy may be administered via one or a combination of several methods, including, but not limited to, external beam therapy, internal radiation therapy, implanted radiation, stereotactic radiotherapy, total body radiation therapy, radiotherapy, and permanent or temporary intratissue brachytherapy. As used herein, the term “proximity radiation therapy” refers to radiotherapy delivered by spatially confined radioactive material inserted into the body at or near a tumor or other site of proliferative tissue disease. The term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Suitable radiation sources for use as cell conditioners in this disclosure include both solid and liquid forms. In non-limiting examples, the radiation source may be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, or another radionuclide emitting photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material may also be a fluid prepared from any solution of the radionuclide(s), e.g., a solution of I-125 or I-131, or the radioactive fluid may be produced using a suitable fluid slurry containing small particles of a solid radionuclide such as Au-198 or Y-90. Furthermore, the radionuclide(s) may be embodied in gels or radioactive microspheres.

[0235] In some embodiments, compound A can make abnormal cells more sensitive to radiotherapy intended to kill or inhibit the proliferation of such cells. Accordingly, the disclosure further relates to a method for sensitizing abnormal cells in mammals to radiotherapy, the method comprising administering to a mammal an amount of the compound of the disclosure that is effective in sensitizing abnormal cells to radiotherapy. The amount of the compound in this method can be determined according to the means for determining an effective amount of such compound described herein. In some embodiments, compound A may be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0236] In some embodiments, the non-pharmacological treatment is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The T cell source is obtained from a subject before proliferation and genetic modification of the T cells. The T cells can be obtained from several sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymic tissue, tissue from infection sites, ascites, pleural fluid, spleen tissue, and tumors. In certain embodiments of this disclosure, any number of T cell lines available in the art may be used. In some embodiments, the T cells are autologous T cells. Whether before or after genetic modification of T cells to express a desired protein (e.g., CAR), T cells are generally, for example, U.S. Patent Nos. 6,352,694, 6,534,055, 6,905,680, 6,692,964, 5,858,358, 6,887,466, 6,905,681, and It can be activated and propagated using the methods described in Nos. 7,144,575, 7,067,318, 7,172,869, 7,232,566, 7,175,843, 7,572,631, 5,883,223, 6,905,874, 6,797,514, and 6,867,041.

[0237] In some embodiments, the compositions and methods described herein may include compound A in combination with one or more claudin-18 targeting agents. The claudin-18 targeting agents may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Claudin-18 (e.g., claudin-18.2, CLDN18.2) has become a promising target for the treatment of patients with gastrointestinal malignancies such as gastric cancer (GC), gastroesophageal junction (GEJ) cancer, esophageal cancer, and pancreatic cancer due to its limited expression in healthy tissue and abnormal overexpression in various malignancies. Several clinical trials of CLDN18.2 targeted therapies, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies, are underway, some showing promising early results. Malignant transformation of gastric epithelial tissue results in disruption of cell polarity, followed by exposure of the CLDN18.2 epitope on the cell surface. While targeted monoclonal antibodies have little access to CLDN18.2 located in tight junction supramolecular complexes in normal tissues, perturbations of cell polarity that expose the CLDN18.2 epitope could theoretically allow CLDN18.2-targeted agents to bind to CLDN18.2 in malignant tissues with minimal off-target effects, making CLDN18.2 an attractive target for therapy. In some embodiments, claudin-18 targeted agents are one or more of zolbetuximab, ASKB589, osemitamab (TST001), PT886 (a bispecific antibody targeting CLDN18.2 and CD47), TJ-CD4B, CMG901 (a cytotoxic payload consisting of an ADC composed of an anti-CLDN18.2 monoclonal antibody conjugated to monomethyl auristatin E), and CT041 (autologous T cells genetically engineered to express CLDN18.2-targeted CARs).In some embodiments, references to the term claudin-18 targeting agent include any such claudin-18 targeting agent disclosed in any one of the following patent applications: WO2024081544, WO2024131683, WO2024137619, WO2024140670, WO2024136594, WO2023034922, WO2023046202, WO2022203090, WO2022133169, WO2022100613, WO2022256449, WO2022136642, WO2021155380, WO2021129765, WO202101188 5, WO2021058000, WO2021218874, WO2021027850, WO2020156554, WO2020025792, WO2020114480, WO2020211792, WO2020239005, WO2019219089, WO2018157147, WO2018108106, WO2016166122, WO2014146778, CN118290582, CN118203658, and CN118286201, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0238] In some embodiments, the therapeutic agent for combination therapy may be a steroid. Therefore, in some embodiments, one or more additional therapies include a steroid. Suitable steroids include 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, crocortol, cloprednol, corticosterone, cortisone, cortivazole, deflazacort, desonide, dexoxymethasone, dexamethasone, diflorasone, diflucortol, difprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, flucortin butyl, flucortolone, fluorometholone, fluperolone acetate, flupredniden acetate, fluprednisolone, and flulandrenolide. Examples include, but are not limited to, fluticasone propionate, formocortal, halcinonide, halobetazole propionate, halomethasone, hydrocortisone, loteprednol etavonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, sodium prednisolone phosphate, prednisone, prednival, prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexaacetonide, and their salts or derivatives.

[0239] Further examples of therapeutic agents that may be used in combination therapy with compound A disclosed herein include compounds described in the following patents: U.S. Patents No. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885. Patent applications Nos. 01 / 37820, 01 / 32651, 02 / 68406, 02 / 66470, 02 / 55501, 04 / 05279, 04 / 07481, 04 / 07458, 04 / 09784, 02 / 59110, 99 / 45009, 00 / 59509, 99 / 61422, 00 / 12089, and 00 / 02871.

[0240] Additional therapeutic agents may be biological agents used to treat cancer or related conditions (e.g., cytokines (e.g., interferons or interleukins such as IL-2)). In some embodiments, the biological agent is a biological agent of the immunoglobulin system, e.g., monoclonal antibodies (e.g., humanized antibodies, fully human antibodies, Fc fusion proteins, or functional fragments thereof) that inflict pain on a target to stimulate an anti-cancer response or antagonize antigens important to cancer. Antibody-drug conjugates are also included.

[0241] The additional therapeutic agent may be an immunomodulator. For example, the additional therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is a drug such as an antibody that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is a drug such as an antibody that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibody, e.g., avelumab, durvalumab, atezolizumab, pizilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or Preusser, M. et al. Checkpoint inhibitors disclosed in al. (2015) Nat. Rev. Neurol. include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirirumab, IPH2101, 1-7F9, and KW-6002. Non-exclusive examples of immunomodulators include the targets specified in Table 1. [Table 1]

[0242] Additional therapeutic agents may include anti-TIGIT antibodies such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (ethigirimab).

[0243] In some embodiments, the combination therapy comprises compound A and a cancer vaccine composition. In some embodiments, the cancer vaccine composition is HB-700, mRNA-4157, mRNA-5671, BNT111, GVAX pancreas, IMA901, DCVax, SOT101, Sipuleucel-T, PROSTVAC-VF, or TG01.

[0244] Additional therapeutic agents may be drugs that treat cancer or related conditions (e.g., cytotoxic agents, non-peptide small molecules, or other compounds useful in treating cancer or related conditions, collectively referred to as “anticancer agents”). Anticancer agents may be, for example, chemotherapeutic agents or targeted therapy agents.

[0245] Anticancer agents include mitotic inhibitors, insertive antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyrotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracendione-substituted ureas, methylhydrazine derivatives, corticosteroids, progestins, estrogens, antiestrogens, androgens, and gonadotropin-releasing hormone analogs. Further anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, one or more additional therapies comprise two or more anticancer agents. Two or more anticancer drugs can be used in a cocktail, either administered in combination or individually. Preferred administration regimens for combination anticancer drugs are known in the art and are described, for example, in Saltz et al., Proc.Am.Soc.Clin.Oncol.18:233a(1999) and Douillard et al., Lancet 355(9209):1041-1047(2000).

[0246] Other non-exclusive examples of anticancer drugs include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents, e.g., thiotepa and cyclophosphamide; alkyl sulfonates, e.g., busulfan, improsulfan, and pigosulfan; aziridines, e.g. , benzodopa, carbocone, metsuredopa, and uredopa; ethyleneimines and methylamelamines, e.g., altoretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bratacin and bratacinone); camptothecin (e.g., synthetic analog topotecan); bryostatin; callistatin; CC-1065 (e.g., its adzeresin, karzeresin, (and beizelesin synthetic analogs); cryptophycin (specifically cryptophycin 1 and cryptophycin 8); dorastatin; duocalmycin (e.g., synthetic analogs KW-2189 and CB1-TM1); eryuterobin; pancratistatin; sarcodictiin A; spongistatin; nitrogen mustard, e.g., chlorambucil, chlornafadin, colophosphamide, estramustine, ifosfamide, mechloretamine, mechlore Tamin oxide hydrochloride, melphalan, nobenbitin, fenestrine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas, e.g., camulstine, chlorozotosine, photemustine, lomustine, nimustine, and ranimustine; antibiotics, e.g., engine antibiotics (e.g., calicheamicin, e.g., calicheamicin gamma II and calicheamicin omega II (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins such as dynemicin A; bisphosphonates such as clodronate; esperamicin;Neocardinostatin chromophore and related pigment protein enediin antiobiotic chromophore, acrasinomycin, actinomycin, autoramycin, azaserin, bleomycin, kactinomycin, calicheamicin, carabicin, kaminomycin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyano Morpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potophyllomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zolbicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); denopterin, pteropterin Folic acid analogs such as trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid infusions such as phloric acid; acegraton; Aldophosphamide glycoside; aminolevulinic acid; enyluracil; amsacrine; bestrabusil; bisanthren; edatrexate; defofamine; demecolsin; diaziquan; elfomithine; eriptinium acetate; epotilon B and other epotilons; etogluside; gallium nitrate; hydroxyurea; lentinan; mytansinoids such as ronidynin, mytansin and ansamitosin; mitogluzone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet;Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS Natural Products, Eugene, OR); Lazoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic acid; Triadicone; 2,2',2''-Trichlorotriethylamine; Trichothecenes such as T-2 toxin, Veraculine A, Loridine A, and Anguidine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphine Amids; thiotepas; taxoids, e.g., Taxol® (paclitaxel), Abraxane® (chromophore-free, albumin-modified nanoparticle formulation of paclitaxel), and Taxotere® (doxetaxel); chlorambucil; tamoxifen (Nolvadex®); raloxifene; aromatase-inhibiting 4(5)-imidazole; 4-hydroxytamoxifen; trioxyfen; keoxyfen; LY 117018; Onapristone; Toremifene (Fareston®); Flutamide, Niltamide, Bicalutamide, Leuprolide, Goserelin; Chlorambucil; Gemzar® Gemcitabine; 6-Thiogunine; Mercaptopurine; Platinum analogs such as cisplatin, oxaliplatin, and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Navel Examples include bine® (vinorelbine); novantron; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicin; capecitabine (e.g., Xeloda®); and any pharmaceutically acceptable salts of the above.

[0247] Non-exclusive examples of additional anticancer drugs include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, Avisin, avagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfarazine, arbocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracendione, anti-CD22 immunotoxin, antitumor drugs (e.g., cell cycle nonspecific antitumor drugs, and other antitumor drugs described herein), antitumor herbs, apadiquon, atiprimod, azathioprine, berotecan, bendamustine, and BIBW. 2992, Bilicodal, Brostarisin, Briostatin, Butionine sulfoximine, CBV (chemotherapy), Calyculine, Dichloroacetate, Discordamorid, Elsamitolu, Enocitabine, Eribulin, Exatecan, Exislind, Ferginol, Forodesine, Phosfestrol, ICE chemotherapy regimen, IT-101, Imexone, Imiquimod, Indocarbazole, Ilofluben, Lanikidal, Lalotaxel, Lenalidomide, Lucanton, Lulutotecan, Maphosfamide, Mitozolomide, Examples include napoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, reximod, rubitecan, SN-38, salinosporamide A, sapacitabine, stanford V, swainsonin, talaporfin, talikidal, tegafur-uracil, temodal, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, bajimezan, vinflunin, ZD6126, and zoskidal.

[0248] Further non-limiting examples of anticancer drugs include vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mitramycin), mitomycin, enzymes (e.g., L-asparaginase, which systemically metabolizes L-asparagine and deprives cells of the ability to synthesize their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., mechloretamine, cyclophosphamide and its analogs, melphalan, and chlorambucil), ethyleneimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), alkyl sulfonates (e.g., busulfan), nitrosole Antiproliferative / antimitotic metabolites and related inhibitors such as a(e.g., carmustine (BCNU) and its analogues, and streptozocin), trazeneth-dacarbadinine (DTIC), folic acid analogues, pyrimidine analogues (e.g., fluorouracil, phloxuridine, and cytarabine), purine analogues (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole) PI3K inhibitors such as exemestane, letrozole, platinum-coordinated complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, DNA binders (e.g., Zalypsis®), PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib;Multi-kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen), and hormone agonists such as leutinizing hormone releasing hormone (LHRH) agonists (e.g., goserelin, leuprorelin, and tryptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN163L), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CSl (e.g., elotuzumab), P13K / Akt inhibitors (e.g., perifosine), PKC inhibitors (e.g., enzastaurin), FTI (e.g., Zarnestra (trademark)), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), and natural products such as cFMS inhibitors (e.g., ARRY-382) and the like. ;

[0249] In some embodiments, the anti-cancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine (registered trademark), sorafenib, or any similar or derivative variant thereof described above. In some embodiments, the anti-cancer agent is JAB-3312.

[0250] In some embodiments, the anti-cancer agent is an antagonist of PD-1 or PD-L1.

[0251] In some embodiments, additional therapeutic agents include immunomodulatory therapies such as ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immune checkpoint inhibitors. In some embodiments, the therapeutic agent can be a pan-RTK inhibitor such as afatinib.

[0252] In some embodiments, additional therapeutic agents are selected from the group consisting of MEK inhibitors, HER2 inhibitors, SHP2 inhibitors, CDK4 / 6 inhibitors, mTOR inhibitors, SOS1 inhibitors, and PD-L1 inhibitors. See, for example, Hallin et al., Cancer Discovery, DOI:10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575:217 (2019). In some embodiments, the RAS(ON) inhibitors of this disclosure are used in combination with MEK inhibitors and SOS1 inhibitors. In some embodiments, the RAS(ON) inhibitors of this disclosure are used in combination with PD-L1 inhibitors and SOS1 inhibitors. In some embodiments, the RAS(ON) inhibitors of this disclosure are used in combination with PD-L1 inhibitors and SHP2 inhibitors. In some embodiments, the RAS(ON) inhibitors of the Disclosure are used in combination with MEK inhibitors and SHP2 inhibitors. In some embodiments, the cancer is colorectal cancer, and the treatment comprises administering the Ras inhibitor of the Disclosure in combination with a second or third therapeutic agent.

[0253] Examples of proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0254] Immunotherapy includes, but is not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically modified T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1, anti-PD-L1, anti-CTLA4, anti-LAGl, and anti-OX40 agents.

[0255] Immunomodulators (IMiDs) are a class of immunomodulatory drugs (drugs that modulate the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0256] Exemplary anti-PD-1 antibodies and their uses are described in Goldberg et al., Blood 2007, 110(1):186-192, Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761, and WO06 / 121168A1), and are described elsewhere in this specification.

[0257] GITR agonists include GITR fusion proteins described in U.S. Patent Nos. 6,111,090, 8,586,023, WO2010 / 003118, and WO2011 / 090754, or, for example, U.S. Patent Nos. 7,025,962, EP1947183, 7,812,135, 8,388,967, 8,591,886, 7,618,632, EP1866339, and WO201 This includes, but is not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the anti-GITR antibodies described in 1 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0258] Another example of a therapeutic agent that may be used in combination with compound A is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions, antibodies, antigen-binding domains, radionuclides, and combinations and conjugates thereof, which are synthetically prepared in vitro. Anti-angiogenic agents may be agonists, antagonists, allosteric modulators, toxins, or, more generally, may act to inhibit or stimulate their targets (e.g., by activating or inhibiting receptors or enzymes), thereby promoting cell death or halting cell proliferation. In some embodiments, one or more additional therapies include anti-angiogenic agents.

[0259] Anti-angiogenic agents can be MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-specific examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include arecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors include WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, and WO99 / 528. As described in 89, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085, and U.S. Patents 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those with little or no activity to inhibit MMP-1. More preferred are those that selectively inhibit MMP-2 or AMP-9 compared to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS 13-0830.

[0260] Further exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to kinase domain receptors), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind to them or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712, US6,413,932), anti-Tweak agents (e.g., antibodies or antigen-binding domains that specifically bind, or soluble Tweak receptor antagonists; see US6,727,225), ADAM distointegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), and anti-eph receptors or anti-ephrin antibodies or antigen-binding domains that specifically bind. Examples include regions (U.S. Patents No. 5,981,245, No. 5,728,813, No. 5,969,110, No. 6,596,852, No. 6,232,447, No. 6,057,124, and their patent family members), anti-PDGF-BB antagonists (e.g., antibody or antigen-binding regions that specifically bind to them), antibody or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibody or antigen-binding regions that specifically bind to them). Additional anti-angiogenic agents include SD-7784 (Pfizer, USA); sirengitide (Merck KGaA, Germany, EPO0770622); pegaptanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, US5712291); ilomastat (Arriva, USA, US5892112); emaxanib (Pfizer, USA, US5792783); and batalanib (Novartis, Switzerland).2-Methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); Anecoltabuacetate (Alcon, USA); Alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands), DAC anti-angiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); Fibrinogen-E fragment (BioActa, UK); Angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); Maspin (Sosei, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP02233610); Platelet factor IV (RepliGen, USA, EP407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL784 (Exelixis, USA); XL647 (Exelixis, USA); MAb, alpha-5 beta-3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, USA); Enzastaurin hydrochloride (Lilly, USA); CEP7055 (Cephalon, USA and Sanofi-Synthelabo, France);BC1 (Genoa Institute of Cancer Research, Italy); rBPI21 and BPI-derived anti-angiogenic drugs (XOMA, USA); PI88 (Progen, Australia); Silengitide (Merck KGaA, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN161 (Attenuon, USA); 2-Methoxyestradiol (Boston Children's Hospital, USA); ZD6474 (AstraZeneca, UK); ZD6126 (Angiogene Pharmaceuticals, UK); PPI2458, (Praecis, USA); AZD9935, (AstraZeneca, UK); AZD2171, (AstraZeneca, UK); batalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitor, (EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA); xantollysole, (Yonsei University, South Korea); vaccine, gene-based, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX103, (University of California at San Diego, USA); PX478, (ProlX, USA); metastatin, (EntreMed, USA); troponin I, (Harvard University, USA); SU6668, (SUGEN, USA); OXI4503, (OXiGENE, USA); o-Guanidine, (Dimensional Pharmaceuticals, USA);Motupolamine C (British Columbia University, Canada); CDP791 (Celltech Group, UK); Atiprimod (pINN) (GlaxoSmithKline, UK); E7820 (Eisai, Japan); CYC381 (Harvard University, USA); AE941 (Aeterna, Canada); Vaccine, Angiogenesis (EntreMed, USA); Urokinase Plasminogen Activator Inhibitor (Dendreon, USA); Ogluphanide (pINN) (Melmotte, USA); HIF-1 Alpha Inhibitor (Xenova, UK); CEP5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR31372 (Korea Research Institute of Chemical Technology, South Korea); GW2286, (GlaxoSmithKline, UK); EHT0101, (ExonHit, France); CP868596, (Pfizer, USA); CP564959, (OSI, USA); CP547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN633, (Kirin Brewery, Japan); Drug delivery system, intraocular, 2-methoxyestradiol; Anguinex (Maastricht University, Netherlands, and Minnesota University, USA); ABT510 (Abbott, USA); AAL993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-alpha inhibitor; SU11248 (Pfizer, USA and SUGEN USA); AB T518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA);MAb, alpha-5 beta (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK, and Johnson & Johnson, USA); GFB116 (South Florida University, USA and Yale University, USA); CS706 (Sankyo, Japan); Combrestatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES2690 (Bayer, Germany); AGM1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA); CV247 (Ivy Medical, UK); CKD732 (Chong Kun Dang, South Korea); Ilsogladine, (Nippon Shinyaku, Japan); RG13577 (Aventis, France); WX360 (Wilex, Germany); Squalamine (Genaera, USA); RPI4610 (Sirna, USA); Heparanase inhibitor (InSight, Israel); KL3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK229561 (Novartis, Switzerland, and Schering AG, Germany); XMP300 (XOMA, USA); VGA1102 (Taisho, Japan); VE-Cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems,USA);TZ93(Tsumura,Japan);TumStatin(Beth Israel Hospital,USA);Examples include cleaved soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0261] Further examples of therapeutic agents that may be used in combination with compound A include agents that specifically bind to and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor) (e.g., antibodies, antigen-binding domains, or soluble receptors), as well as antibodies or antigen-binding domains that specifically bind to the receptor c-Met.

[0262] Another example of a therapeutic agent that may be used in combination with compound A is an antineoplastic agent. In some embodiments, one or more additional therapies include an antineoplastic agent. Non-limiting examples of antineoplastic agents include acemannan, acralubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amiphostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, algravin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, bromodeoxyuridine, capecitabine, cermoloukin, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, and DA 3030 (Dong-A), daclizumab, denileukin difutox, deslorerin, dexrazoxane, dilazep, docetaxel, docosanol, doxelcalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, ederfosine, edrecolomab, eflornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, exislind, fadrozol, filgrastim, finasteride, fludarabine phosphate, formestan, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination Combined, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin (imiquimod), interferon alpha, interferon alpha, natural type, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-NI, interferon alpha-n3, interferon alpha-con-1, interferon alpha, natural type, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural type interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguan, irinotecan, ilsoglazine,Lanreotide, LC 9018 (Yakult), Leflunomide, Lenograstim, Lentinan sulfate, Letrozole, Leukocyte alpha interferon, Leuprorelin, Levamizole + Fluorouracil, Rialozol, Lovaplatin, Ronidamin, Lovastatin, Masopropyl, Melalsoprole, Metoclopramide, Mifepristone, Miltefosine, Millimostim, Mispaired double-stranded RNA, Mitoguazone, Mitractol, Mitoxantrone, Morglamostim, Nafarelin, Naloxone + Pentazocine, Naltograstim, Nedaplatin, Nil Tamide, Noscapine, Novel Erythropoiesis-Promoting Protein, NSC631570 Octreotide, Oprelbequin, Osateron, Oxaliplatin, Paclitaxel, Pamidronic Acid, Pegaspargase, Peginterferon Alpha-2b, Pentosan, Sodium Polysulfate, Pentostatin, Picibanil, Pirarubicin, Rabbit Antithymocyte Polyclonal Antibody, Polyethylene Glycol Interferon Alpha-2a, Porfimer Sodium, Raloxifene, Larcitrexed, Rasburiemb (Diment), etidronate rhenium Re186, RII retinamide, rituximab, romultide, samarium (153Sm) lexidonam, salglamostim, schizophyllan, sobuzoxane, sonelmin, strontium-89 chloride, suramin, tasonelmin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecoxide, thalidomide, thymalfacin, thyroid-stimulating hormone alpha, topotecan, toremifene, tositumomab-iodine-131, trastuzumab, treosulfan, tretinoin Noin, trilostane, trimethrexate, triptorelin, tumor necrosis factor alpha, natural type, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma solubilizing solution vaccine, barrubicin, verteporfin, vinorelbine, bilirulysine, dinostatin stimalamer or zoledronic acid; Abarelix; AE941 (Aeterna), ambamustin, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), decitabine, dexaaminoglutethimide, diazicon, EL532 (Elan),EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, gallocitabine, gastrin-17 immunogene, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxyfen, LDI200 (Milkhaus), religistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine-131 MAb (Techni clone), polymorphoemic mucin-yttrium 90 MAb (Antisoma), marimast, menogalil, mitumomab, motexafine, gadolinium, MX 6 (Galderma), nelarabine, noratexed, P30 protein, pegvisomant, pemetrexed, porphyromycin, prinomast, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparphosic acid, SRL172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, saliblastin, thrombopoietin, tin ethylethiopurine, tirapazamin, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysis product vaccine (New York Medical Examples include the College vaccine, a viral melanoma cell solubilization vaccine (Royal Newcastle Hospital), or Valspodar.

[0263] Additional therapeutic agents that may be used in combination with compound A include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; Atasicept; CP-870893; Lucatumumab; Dasetuzumab; Muromonab-CD3; Ipirumumab; MEDI4736 (Imfinzi (registered trademark)); MSB0010718C; AMP 224; Adalimumab (Humira®); Adtrastuzumab emtansine (Kadcyla®); Aflibercept (Eylea®); Alemtuzumab (Campath®); Basiliximab (Simulect®); Belimumab (Benlysta®); Basiliximab (Simulect®); Belimumab (Benlysta®); Brentuximab vedotin (Adcetris®); Canakinumab (Ilaris®); Certolizumab pegol (Cimzia®); Daclizumab (Zenapax®); Daratumumab (Darzale x(registered trademark)); denosumab (Prolia(registered trademark)); eculizumab (Soliris(registered trademark)); efalizumab (Raptiva(registered trademark)); gemtuzumab ozogamicin (Mylotarg(registered trademark)); golimumab (Simponi(registered trademark)); ibritumomab tiuxetan (Zevalin(registered trademark)); infliximab (Remicade(registered trademark)); motabizumab (Numax(registered trademark)); natalizumab (Tysabri(registered trademark)); obinutuzumab (Gazyva(registered trademark)); ofatumumab (Arzerra(registered trademark)); omalizumab (Xolair(registered trademark)); palivizumab (Synagis(registered trademark));Examples include pertuzumab (Perjeta®), pertuzumab (Perjeta®), ranibizumab (Lucentis®), laxibakumab (Abthrax®), tocilizumab (Actemra®), tositumomab, tositumomab-i-131, tositumomab and tositumomab-i-131 (Bexxar®), ustekinumab (Stelara®), AMG 102, AMG 386, AMG 479, AMG 655, AMG 706, AMG 745, and AMG 951.

[0264] The methods described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the disclosed herein are co-administered with other therapies described herein. When used in combination therapy, the compounds disclosed herein may be administered simultaneously with or separately from a second agent. This combined administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration of different dosage forms, and separate administrations. That is, the compounds described herein and any of the agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention and any of the therapies described herein can be administered simultaneously, with both agents present in separate formulations. Another alternative is that the compounds of the disclosed invention may be administered followed by any of the therapies described herein, or vice versa. In some embodiments of separate administration protocols, the compounds of the present invention and any of the therapies described herein are administered at intervals of minutes, hours, or days.

[0265] In some embodiments of any of the methods described herein, the first therapy and one or more additional therapies are administered simultaneously or sequentially in any order. The first therapeutic agent may be administered immediately before or after one or more additional therapies, or up to 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days before or after.

[0266] The Disclosure also features a kit comprising (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the Invention), and (b) a package containing instructions for carrying out any of the methods described herein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the Invention), (b) one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents), and (c) a package containing instructions for carrying out any of the methods described herein.

[0267] One aspect of the present disclosure relates to combining separate pharmaceutical compositions in the form of a kit, for the purpose of treating a disease or related symptoms using a combination of pharmaceutically active compounds that can be administered separately. The kit may comprise two separate pharmaceutical compositions, i.e., the compounds of the present invention, and one or more additional therapies. The kit may comprise containers for housing the separate compositions, such as divided bottles or divided foil packets. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions for using the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing healthcare professional.

[0268] Embodiment Embodiment 1: A method for treating cancer in a human subject requiring cancer treatment, wherein the method involves compound A in a total daily dose of 50 mg to 800 mg: [ka] The method comprising orally administering a pharmaceutically acceptable salt thereof to the subject.

[0269] Embodiment 2: The method according to Embodiment 1, wherein the method comprises a total daily dose of compound A of 60 mg to 800 mg to the subject.

[0270] Embodiment 3: The method according to Embodiment 1, wherein the method comprises administering compound A to the subject in a total daily dose of 70 mg to 800 mg.

[0271] Embodiment 4: The method according to Embodiment 1, wherein the method comprises administering 80 mg to 500 mg of compound A to the subject.

[0272] Embodiment 5: The method according to Embodiment 1, wherein the method comprises administering compound A to the subject in a total daily dose of 100 mg to 800 mg.

[0273] Embodiment 6: The method according to Embodiment 1, wherein the method comprises administering compound A to the subject in a total daily dose of 120 mg to 800 mg.

[0274] Embodiment 7: The method according to Embodiment 1, wherein the method comprises administering compound A to the subject in a total daily dose of 160 mg to 800 mg.

[0275] Embodiment 8: The method according to Embodiment 1, wherein the method comprises administering compound A to the subject in a total daily dose of 200 mg to 800 mg.

[0276] Embodiment 9: The method according to Embodiment 1, wherein the method comprises administering compound A to the subject in a total daily dose of 250 mg to 800 mg.

[0277] Embodiment 10: The method according to Embodiment 1, wherein the method comprises administering compound A to the subject in a total daily dose of 300 mg to 800 mg.

[0278] Embodiment 11: The method according to Embodiment 1, wherein the method comprises a total daily dose of compound A of 350 mg to 800 mg to the subject.

[0279] Embodiment 12: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 400 mg to 800 mg to the subject.

[0280] Embodiment 13: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 450 mg to 800 mg to the subject.

[0281] Embodiment 14: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 500 mg to 800 mg to the subject.

[0282] Embodiment 15: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 550 mg to 800 mg to the subject.

[0283] Embodiment 16: The method according to Embodiment 1, wherein the method includes administering a total daily dose of 600 mg to 800 mg to the subject.

[0284] Embodiment 17: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 650 mg to 800 mg to the subject.

[0285] Embodiment 18: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 700 mg to 800 mg to the subject.

[0286] Embodiment 19: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 750 mg to 800 mg to the subject.

[0287] Embodiment 20: The method according to Embodiment 1, wherein the method includes administering a total daily dose of 750 mg to 800 mg to the subject.

[0288] Embodiment 21: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 750 mg to 800 mg to the subject.

[0289] Embodiment 22: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 225 mg to 575 mg to the subject.

[0290] Embodiment 23: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 250 mg to 550 mg to the subject.

[0291] Embodiment 24: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 275 mg to 525 mg to the subject.

[0292] Embodiment 25: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 300 mg to 500 mg to the subject.

[0293] Embodiment 26: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 325 mg to 475 mg to the subject.

[0294] Embodiment 27: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 350 mg to 450 mg to the subject.

[0295] Embodiment 27: The method according to Embodiment 1, wherein the method comprises administering a total daily dose of 375 mg to 425 mg to the subject.

[0296] Embodiment 28: The method according to any one of Embodiments 1 to 27, wherein compound A is administered once or twice daily.

[0297] Embodiment 29: The method according to Embodiment 1 or 2, wherein the method comprises administering 60 mg of compound A to the subject.

[0298] Embodiment 30: The method according to any one of Embodiments 1 to 3, wherein the method comprises administering 70 mg of compound A to the subject.

[0299] Embodiment 31: The method according to any one of Embodiments 1 to 4, wherein the method comprises administering 80 mg of compound A to the subject.

[0300] Embodiment 32: The method according to any one of Embodiments 1 to 5, wherein the method comprises administering 100 mg of compound A to the subject.

[0301] Embodiment 33: The method according to any one of Embodiments 1 to 6, wherein the method comprises administering 120 mg of compound A to the subject.

[0302] Embodiment 34: The method according to any one of Embodiments 1 to 6, wherein the method comprises administering 160 mg of compound A to the subject.

[0303] Embodiment 35: The method according to any one of Embodiments 1 to 7, wherein the method comprises administering 200 mg of compound A to the subject.

[0304] Embodiment 36: The method according to any one of Embodiments 1 to 8, wherein the method comprises administering 250 mg of compound A to the subject.

[0305] Embodiment 37: The method according to any one of Embodiments 1 to 9, wherein the method comprises administering 300 mg of compound A to the subject.

[0306] Embodiment 38: The method according to any one of Embodiments 1 to 10, wherein the method comprises administering 350 mg of compound A to the subject.

[0307] Embodiment 39: The method according to any one of Embodiments 1 to 11, wherein the method comprises administering 400 mg of compound A to the subject.

[0308] Embodiment 40: The method according to any one of Embodiments 1 to 12, wherein the method comprises administering 450 mg of compound A to the subject.

[0309] Embodiment 41: The method according to any one of Embodiments 1 to 13, wherein the method comprises administering 500 mg of compound A to the subject.

[0310] Embodiment 42: The method according to any one of Embodiments 1 to 14, wherein the method comprises administering 550 mg of compound A to the subject.

[0311] Embodiment 43: The method according to any one of Embodiments 1 to 15, wherein the method comprises administering 600 mg of compound A to the subject.

[0312] Embodiment 44: The method according to any one of Embodiments 1 to 16, wherein the method comprises administering 650 mg of compound A to the subject.

[0313] Embodiment 45: The method according to any one of Embodiments 1 to 17, wherein the method comprises administering 700 mg of compound A to the subject.

[0314] Embodiment 46: The method according to any one of Embodiments 1 to 18, wherein the method comprises administering 750 mg of compound A to the subject.

[0315] Embodiment 47: The method according to any one of Embodiments 1 to 18, wherein the method comprises administering 800 mg of compound A to the subject.

[0316] Embodiment 48: The method according to Embodiment 1, wherein the method comprises administering 175 mg to 325 mg of compound A twice a day.

[0317] Embodiment 49: The method according to Embodiment 1, wherein the method comprises administering 200 mg to 300 mg of compound A twice a day.

[0318] Embodiment 50: The method according to Embodiment 1, wherein the method comprises administering 225 mg to 275 mg of compound A twice a day.

[0319] Embodiment 51: The method according to Embodiment 1, wherein the method comprises administering 200 mg of compound A twice a day.

[0320] Embodiment 52: The method according to Embodiment 1, wherein the method comprises administering 300 mg of compound A twice a day.

[0321] Embodiment 53: The method according to Embodiment 1, wherein the method comprises administering 400 mg of compound A twice daily (BID).

[0322] Embodiment 54: The method according to any one of Embodiments 1 to 53, wherein compound A is administered to the subject daily for at least one day a week.

[0323] Embodiment 55: The method according to any one of Embodiments 1 to 53, wherein compound A is administered to the subject once a day on the 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th days of each of the 7 days.

[0324] Embodiment 56: The method according to any one of Embodiments 1 to 55, wherein the cancer comprises a RAS G12C mutation.

[0325] Embodiment 57: The method according to Embodiment 56, wherein the cancer is pancreatic cancer.

[0326] Embodiment 58: The method according to Embodiment 56, wherein the cancer is lung cancer.

[0327] Embodiment 59: The method according to Embodiment 56, wherein the cancer is colorectal cancer.

[0328] Embodiment 60: The method according to any one of Embodiments 1 to 59, further comprising administering an additional therapeutic agent.

[0329] Embodiment 61: The method according to Embodiment 60, wherein the additional therapeutic agent is a pan-KRAS inhibitor.

[0330] Embodiment 62: The method according to Embodiment 60, wherein the additional therapeutic agent is a KRASG12C(OFF) inhibitor.

[0331] Embodiment 63: The method according to Embodiment 60, wherein the additional therapeutic agent is a RAS(ON) multiselective inhibitor.

[0332] Embodiment 64: The method according to Embodiment 60, wherein the additional therapeutic agent comprises an SHP2 inhibitor and a PD-L1 inhibitor.

[0333] Embodiment 65: The method according to Embodiment 60, wherein the additional therapy comprises a second RAS inhibitor and a PD-L1 inhibitor.

[0334] Embodiment 66: The method according to Embodiment 60, wherein the additional therapy is pembrolizumab or a biosimilar thereof.

[0335] Embodiment 67: The method according to Embodiment 60, wherein the additional therapy is cetuximab or a biosimilar thereof.

[0336] Embodiment 68: A method for treating cancer containing a RAS G12C mutation in a subject requiring treatment for cancer containing a RAS G12C mutation, wherein the method comprises orally administering compound A in a total daily dose of 200 mg to 800 mg, and compound A is administered to the subject twice a day.

[0337] Embodiment 69: The method according to Embodiment 68, further comprising screening or monitoring the subject for regulated cardiac function.

[0338] Embodiment 70: The method according to Embodiment 68, wherein the subject does not have congenital QT prolongation syndrome or simultaneous QTc prolongation.

[0339] Embodiment 71: The method according to Embodiment 68, wherein the subject has discontinued or avoided using a product known to potentially extend the QTc interval.

[0340] Embodiment 72: The method according to Embodiment 68, wherein a change in the QTc interval is detected during treatment with compound A.

[0341] Embodiment 73: The method according to Embodiment 72, wherein the change in the QTc interval is an absolute value of QTc greater than 500 ms, or an increase of more than 60 ms from the baseline.

[0342] Embodiment 74: The method according to Embodiment 72 or 73, wherein the method comprises pausing the administration of compound A for a period of time sufficient to allow the QTc interval to become smaller than approximately 481 ms or to return to the baseline.

[0343] Embodiment 75: The method according to Embodiment 74, wherein the method comprises reducing the dose of compound A.

[0344] Embodiment 76: The method according to any one of Embodiments 1 to 75, wherein the subject has received at least one prior systemic cancer therapy.

[0345] Embodiment 77: The method according to any one of Embodiments 68 to 76, wherein the cancer is NSCLC.

[0346] Embodiment 78: The method according to any one of Embodiments 68 to 76, wherein the cancer is CRC.

[0347] Embodiment 79: The subject previously used KRAS G12C The method according to any one of embodiments 68 to 78, wherein the patient has been treated with an (OFF) inhibitor.

[0348] Embodiment 80: The subject previously used KRAS G12C The method according to any one of embodiments 68 to 78, wherein the patient has not been treated with an (OFF) inhibitor.

[0349] Embodiment 81: The method according to any one of Embodiments 1 to 80, wherein compound A is administered without food.

[0350] Embodiment 82: The method according to any one of Embodiments 1 to 80, wherein the subject does not ingest food for at least 4 hours after administration of compound A.

[0351] Embodiment 83: The method according to any one of Embodiments 1 to 80, wherein the subject does not ingest food for at least 8 hours prior to administration of compound A.

[0352] Embodiment 84: The method according to any one of Embodiments 1 to 80, wherein the subject does not consume food for at least several hours before administration of compound A, and the subject does not consume food for at least four hours after administration of compound A.

[0353] Embodiment 85: The method according to any one of Embodiments 1 to 80, wherein the subject is in a fasting state at the time of administration of compound A.

[0354] Embodiment 86: The method according to Embodiment 85, wherein the subject does not ingest water one hour before and / or one hour after the administration of compound A. [Examples]

[0355] This disclosure is further illustrated by the following embodiments, which should not be considered to limit the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the embodiments are provided to illustrate specific embodiments and are not intended to imply any limitation on the scope of this disclosure. It should also be understood that various other embodiments, modifications, and equivalents can be taken, which themselves may be suggested to those skilled in the art, without departing from the spirit of this disclosure or the appended claims.

[0356] Example 1. Progressive KRAS G12C Study design for compound A monotherapy in patients with mutant solid tumors As described herein, compound A is a mutant RAS G12C Compound A is an orally bioavailable RAS(ON) inhibitor of a potent covalent triplicate, selectively targeting the active GTP-binding state of KRAS. Compound A binds to cyclophyllin A (CypA), an intracellular protein that is ubiquitously and abundantly expressed in normal tissues and tumors, with particularly high expression in tumors and evidence suggesting its possible association with malignant transformation. The binding of compound A to CypA results in a two-component complex, which then binds to KRAS. G12C It binds to (ON) and forms a stable triplicate complex, and KRAS is activated by compound A. G12C This results in irreversible covalent modification of the unique Cys-12 residue. The three complexes are KRAS G12C By disrupting the interaction between (ON) and the effector, downstream signaling is suppressed, and KRAS G12C Compound A induces growth inhibition and apoptosis in vitro in multiple human cancer cell lines carrying the mutation. Compound A shows remarkable antitumor activity in vivo and in human KRAS G12C It induces dose-dependent and sustained tumor regression in multiple xenograft models of cancer.

[0357] This case involves a patient with progressive KRAS, the first of whom was administered medication in September 2022. G12CThis document describes the study design for a Phase 1 / 1b study of compound A in patients with solid tumors. This study consists of two parts: Part 1: Dose Elevation and Part 2: Dose Expansion (Figure 1). Part 1—Dose Elevation—will involve safety and tolerability assessments, and a candidate recommended Phase 2 dose and schedule (RP2DS) will be determined for further testing in the dose expansion part. Part 2 of this study will involve KRAS G12C This study evaluates the safety and antitumor efficacy of candidate RP2DS in mutant solid tumors.

[0358] The dose escalation cohort includes subjects with KRASG12C tumors (including non-small cell lung cancer [NSCLC] and colorectal cancer [CRC]) who have not been previously exposed to KRASG12C(OFF) inhibitors (KRASG12Ci naives). Additional expansion cohorts will be added if it is justified to explore alternative candidate RP2DS or target populations. The final estimate of the RP2DS will be evaluated and confirmed including all subjects from the dose escalation and dose escalation cohorts. All toxicities, including toxicities during cycle 1 and late-stage toxicities outside of cycle 1, will be considered in the determination of the RP2DS.

[0359] Part 1: Dose-escalation design Dose escalation was induced by a time-to-event Bayesian optimal interval (TITE-BOIN) design (Yuan, 2018) with a target dose-limiting toxicity (DLT) rate of 0.3 and an acceptable toxicity interval of [0.236, 0.333]. DLT assessments were performed in populations where DLT assessment was possible. Enrollment began with an initial cohort size of 3-4 subjects at each dose level / schedule. At the maximum tolerable dose (MTD), at least 6 subjects were assessed.

[0360] The starting dose of compound A was 50 mg orally once daily (QD). The dose levels evaluated during dose escalation are summarized in Table 2 below. The first cycle of treatment (i.e., the first 21 days after the start of treatment) constitutes the DLT evaluation period. [Table 2]

[0361] In addition to the planned dose level, the extent of further dose exploration (e.g., intermediate dose levels) will be implemented based on newly emerging safety and / or pharmacokinetic (PK) data, as well as recommendations from the Dose Committee (DC). Safety signals are closely monitored, and smaller escalation increments may be implemented.

[0362] Alternative dosing schedules were explored based on newly emerging safety and PK data. These alternative schedules include, but are not limited to, administering compound A twice daily (BID) instead of QD.

[0363] Backfill cohort To better characterize the safety, PK, and preliminary activity of compound A, additional subjects were enrolled in a backfill cohort that was considered safe and tolerable, and which would become open once the dose cleared the DLT evaluation. The backfill slot was initially KRAS G12C Patients with a variant solid tumor and a history of KRAS G12C (OFF) May be reserved for subjects not treated with inhibitors. The backfill cohort may be selected if a partial response (PR) or better response to compound A is observed in this population during dose escalation. G12C (OFF) KRAS with prior exposure to inhibitors G12C We will open registration for subjects that possess NSCLC.

[0364] Backfill enrollment occurs simultaneously with dose escalation; however, if there are eligible subjects for both backfill and dose escalation, priority may be given to enrolling in the dose escalation cohort.

[0365] Part 2: Dosage Expansion Enrollment in Part 2 (dose escalation) began when the first candidate drug, RP2DS, was selected and proceeded in parallel with Part 1 (dose escalation).

[0366] Part 2 will enroll one or more expanded cohorts treated with candidate RP2DS. The dose-expanded cohort will include those previously treated with KRAS. G12C (OFF) KRAS that have never been exposed to inhibitors G12C This includes subjects with NSCLC and CRC. Additional expanded cohorts will be added if it is justified to explore alternative candidate RP2DS or target populations.

[0367] Each expanded cohort will enroll approximately 30 (up to approximately 40) evaluable subjects, and up to 12 subjects will be enrolled in the food effects cohort. Part 2 – Dose Expansion can enrol...

Claims

1. A method for treating cancer in a human subject requiring cancer treatment, wherein the method involves administering compound A to the subject in a total daily dose of 50 mg to 800 mg: 【Chemistry 1】 The method comprising administering orally.

2. The method according to claim 1, wherein the method comprises administering 100 mg to 800 mg of compound A to the subject.

3. The method according to claim 1, wherein the method comprises administering 200 mg to 800 mg of compound A to the subject.

4. The method according to claim 1, wherein the method comprises administering 300 mg to 800 mg of compound A to the subject.

5. The method according to claim 1, wherein the method comprises administering 400 mg to 800 mg of compound A to the subject.

6. The method according to claim 1, wherein the method comprises administering 500 mg to 800 mg of compound A to the subject.

7. The method according to claim 1, wherein the method comprises administering 600 mg to 800 mg of compound A to the subject.

8. The method according to claim 1, wherein the method comprises administering 700 mg to 800 mg of compound A to the subject.

9. The method according to claim 1, wherein the method comprises administering 200 mg to 300 mg of compound A to the subject.

10. The method according to any one of claims 1 to 9, wherein compound A is administered once or twice a day.

11. The method according to claim 1 or 2, wherein the method comprises administering 100 mg of compound A to the subject.

12. The method according to any one of claims 1 to 3, wherein the method comprises administering 200 mg of compound A to the subject.

13. The method according to any one of claims 1 to 4, wherein the method comprises administering 300 mg of compound A to the subject.

14. The method according to any one of claims 1 to 5, wherein the method comprises administering 400 mg of compound A to the subject.

15. The method according to any one of claims 1 to 6, wherein the method comprises administering 500 mg of compound A to the subject.

16. The method according to any one of claims 1 to 7, wherein the method comprises administering 600 mg of compound A to the subject.

17. The method according to any one of claims 1 to 8, wherein the method comprises administering 700 mg of compound A to the subject.

18. The method according to any one of claims 1 to 8, wherein the method comprises administering 800 mg of compound A to the subject.

19. The method according to any one of claims 1 to 18, wherein compound A is administered once, two, three, four, five, six, or seven times a week.

20. The method according to any one of claims 1 to 19, wherein the subject is administered compound A for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least twelve months, at least fifteen months, at least eighteen months, at least twenty-one months, or at least twenty-three months.

21. The method according to any one of claims 1 to 19, wherein compound A is administered in a treatment cycle, each treatment cycle being 7 days, 14 days, 21 days, 28 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year.

22. The method according to claim 21, wherein the subject receives one, two, three, or more treatment cycles.

23. The method according to any one of claims 1 to 22, wherein the cancer includes a RAS mutation.

24. The method according to claim 23, wherein the RAS mutation is G12C.

25. The method according to any one of claims 1 to 24, wherein the cancer is pancreatic cancer.

26. The method according to any one of claims 1 to 24, wherein the cancer is lung cancer.

27. The method according to any one of claims 1 to 24, wherein the cancer is colorectal cancer.

28. The method according to claim 26, wherein the lung cancer is non-small cell lung cancer.

29. The method according to claim 23 or 24, wherein the RAS protein is KRAS.

30. The method according to any one of claims 1 to 29, further comprising administering an additional therapeutic agent.

31. The method according to claim 30, wherein the additional therapeutic agent is a RAS(ON) multiselective inhibitor.

32. The method according to claim 30, wherein the additional therapeutic agent is a pan-KRAS inhibitor.

33. The method according to claim 30, wherein the additional therapeutic agent is a PD-1 and / or PD-L1 inhibitor.

34. A method for treating cancer containing the RAS G12C mutation in a human subject requiring treatment for cancer containing the RAS G12C mutation, the method comprising orally administering compound A to the subject in a total daily dose of 200 mg to 600 mg, wherein compound A is administered to the subject twice a day.

35. The method according to claim 34, further comprising screening or monitoring the subject for regulated cardiac function.

36. The method according to claim 35, wherein the subject does not have congenital QT prolongation syndrome or simultaneous QTc prolongation.

37. The method according to claim 35, wherein the subject has discontinued or avoided using a product known to potentially extend the QTc interval.

38. The method according to claim 35, wherein a change in the QTc interval is detected during treatment with compound A.

39. The method according to claim 38, wherein the change in the QTc interval is an absolute value of QTc exceeding 500 ms, or an increase of more than 60 ms from the baseline.

40. The method according to claim 38 or 39, wherein the method comprises pausing the administration of compound A for a period of time sufficient to allow the QTc interval to become less than approximately 481 ms or to return to the baseline.

41. The method according to claim 40, wherein the method includes reducing the dose of compound A.

42. A method for treating non-small cell lung cancer (NSCLC) containing a RAS G12C mutation in a human subject requiring treatment for NSCLC, wherein the method comprises orally administering compound A to the subject in a total daily dose of 200 mg to 600 mg, wherein compound A is administered twice daily.

43. The method according to claim 42, wherein the method comprises administering 200 mg of compound A to the subject twice a day.

44. The method according to claim 42 or 43, wherein the subject has received at least one prior cancer treatment.

45. The method according to any one of claims 42 to 44, wherein the subject has locally progressive or metastatic NSCLC.

46. The above is the previous KRAS Ｇ１２Ｃ The method according to any one of claims 42 to 45, wherein the patient is receiving an (OFF) inhibitor.

47. The aforementioned target is KRAS Ｇ１２Ｃ The method according to any one of claims 42 to 45, which is naive to (OFF) inhibitors.

48. A method for treating colorectal cancer (CRC) containing a RAS G12C mutation in a human subject requiring treatment for colorectal cancer (CRC), wherein the method comprises orally administering to the subject a total daily dose of compound A or a pharmaceutically acceptable salt thereof in a total daily dose of 200 mg to 600 mg, wherein compound A is administered twice daily.

49. The method according to claim 48, wherein the method comprises administering 200 mg or 300 mg of compound A to the subject twice a day.

50. The method according to claim 48 or 49, wherein the subject has received at least one prior cancer treatment.

51. The method according to any one of claims 48 to 50, wherein the subject is naive to a KRASG12C (OFF) inhibitor.

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