RMC-6291 for treating RAS protein related diseases or disorders

Abstract

The present disclosure features methods of treating RAS disorders using Compound (A) or a pharmaceutically acceptable salt thereof. The disclosure also features methods of treating RAS disorders (e.g., cancer) comprising a combination of Compound (A) or a pharmaceutically acceptable salt thereof with an additional therapeutic agent. Compound (A) is a compound having a structure (A):

Description

Cross-references to related applications

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

[0002] Most small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the activity of those proteins. For example, cholesterol-lowering drugs called statins bind to the active site of HMG-CoA reductase, thus preventing the enzyme from binding to its substrate. The fact that many such drug / target interaction pairs are known might mislead some into believing that, with a reasonable amount of time, effort, and resources, small molecule regulators could be discovered for most (if not all) proteins. But this is far from the truth. Currently, it is estimated that only about 10% of all human proteins are suitable targets for small molecules. The remaining 90% are currently considered intractable or difficult to treat with the aforementioned small molecule drugs. These targets are often referred to as “undruggable.” These undruggable targets comprise a large and largely unexplored library of medically important human proteins. Therefore, there is great interest in discovering new molecular modalities that can modulate the function of these undruggable targets.

[0003] The literature has well established that RAS proteins (KRAS, HRAS, and NRAS) play a crucial role in various human cancers, thus making them suitable targets for anticancer therapies. In fact, approximately 30% of all human cancers in the United States are caused by mutations in RAS proteins, many of which are fatal. Dysregulation of RAS proteins caused by activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations of RAS are frequently found in human cancers. For example, an activating mutation at codon 12 in the RAS protein significantly biases the RAS mutant protein population towards the "on" (GTP-binding) state (RAS(ON)) by inhibiting GTPase activator protein (GAP) dependence and intrinsic GTP hydrolysis rate, leading to oncogenic MAPK signaling. Notably, RAS exhibits a picomolar affinity for GTP, allowing it to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13C) and 61 (e.g., Q61K) in RAS also induce oncogenic activity in some cancers.

[0004] In normal cells, RAS proteins play a crucial role in regulating cell growth, differentiation, and survival. They act as molecular switches, transmitting signals from cell surface receptors to intracellular pathways that control key cellular processes. Genetic studies have shown that complete deletion of the RAS gene is lethal in mouse models and leads to a lack of cell proliferation in vitro (Drosten et al., Oncogene 33, 2857-2865 (2014); Drosten et al., EMBO J. 29, 1091-1104 (2010)). Furthermore, conditional knockout of KRAS in adult bone marrow has been shown to induce significant hematopoietic defects, including splenomegaly, enlarged neutrophil compartments, and reduced B cell numbers (Zhang et al., Stem Cells; 34(7):1859-71 (2016)). Targeting mutant forms of RAS, rather than wild-type RAS, has become a strategy for treating RAS-mutant cancers because it is specifically involved in oncogenic signaling. Despite extensive drug discovery efforts targeting RAS over the past few decades, only two agents targeting the KRAS G12C mutant have been approved in the United States (sotorasib and adagrasib). However, both of these drugs target the "OFF" form of KRAS (KRAS G12C mutant). G12C (OFF) inhibitors), and are limited in both depth and duration of response. Although the reasons for this limitation are multifaceted, cancer cells appear to circumvent the inactive state selectively by increasing the amount of drug-insensitive / GTP-bound KRASG12C.

[0005] Further efforts are needed to discover additional drugs targeting cancers driven by RASG12C mutations. Summary of the Invention

[0006] This article provides a method for treating RAS protein-related conditions using compound A or a pharmaceutically acceptable salt thereof, wherein compound A or a pharmaceutically acceptable salt thereof is a RAS inhibitor.

[0007] Compound A In one aspect, this disclosure is characterized by a method for treating RAS protein-related conditions (e.g., cancer) in human subjects in need. The method includes orally administering to the subject 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 to 700 mg, 120 mg to 700 mg, 160 mg to 700 mg, 200 mg to 700 mg, 250 mg to 700 mg, 300 mg to 800 mg, 400 mg to 800 mg, 450 mg to 800 mg, 500 mg to 800 mg, 550 mg to 800 mg, 60 mg to 700 mg, 80 mg to 700 mg, 120 mg to 700 mg, 160 mg to 700 mg, 200 mg to 700 mg, 250 mg to 700 mg, 30 ... mg to 700 mg, 350 mg to 700 mg, 400 mg to 700 mg, 450 mg to 700 mg, 500 mg to 700 mg, 550 mg to 700 mg, 600 mg to 700 mg, 650 mg to 700 mg, 60 mg to 600 mg, 80 mg to 600 mg, 120 mg to 600 mg, 160 mg to 600 mg, 200 mg to 600 mg, 250 mg to 600 mg, 300 mg to 600 mg, 350 mg to 600 mg, 400 mg to 600 mg, 450 mg to 600 mg, 500 mg to 600 mg, 550 mg to 600 mg, 60 mg to 500 mg, 80 mg to 500 mg, 120 mg to 500 mg, 160 mg to 500 mg, 200 mg to 500 mg, 2 ... mg to 500 mg, 250 mg to 500 mg, 300 mg to 500 mg, 350 mg to 500 mg, 400 mg to 500 mg, 450 mg to 500 mg, 60 mg to 400 mg, 80 mg to 400 mg, 120 mg to 400 mg, 160 mg to 400 mg, 200 mg to 400 mg, 250 mg to 400 mg, 300 mg to 400 mg, 350 mg to 400 mg, 50 mg to 300 mg, 60 mg to 300 mg, 80 mg to 300 mg, 120 mg to 300 mg, 160 mg to 300 mg, 200 mg to 300 mgCompound A (total daily dose between 250 mg and 300 mg, 50 mg and 250 mg, 60 mg and 250 mg, 80 mg and 250 mg, 120 mg and 250 mg, 160 mg and 250 mg, 50 mg and 200 mg, 60 mg and 200 mg, 80 mg and 200 mg, 120 mg and 200 mg, 160 mg and 200 mg, 50 mg and 160 mg, 60 mg and 160 mg, 80 mg and 160 mg, 120 mg and 160 mg, 50 mg and 120 mg, 60 mg and 120 mg, 80 mg and 120 mg, 50 mg and 80 mg, 60 mg and 80 mg, 70 mg and 80 mg, 50 mg and 100 mg, 60 mg and 100 mg or between 80 mg and 100 mg).

[0008] In some embodiments, the method includes administering a total daily dose of 50 mg to 800 mg to the subject (e.g., 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, 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, 40 ... Compound A (total daily dose of 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).

[0009] In some embodiments, the method includes administering to a subject a total daily dose of compound A 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.

[0010] In some embodiments, the method includes administering 80 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 90 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 100 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 120 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 160 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 200 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 250 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 300 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 350 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 400 mg to 500 mg of compound A to a subject. In some embodiments, the method includes administering 450 mg to 500 mg of compound A to a subject.

[0011] In some embodiments, the method includes administering 80 mg to 400 mg of compound A to a subject. In some embodiments, the method includes administering 90 mg to 400 mg of compound A to a subject. In some embodiments, the method includes administering 100 mg to 400 mg of compound A to a subject. In some embodiments, the method includes administering 120 mg to 400 mg of compound A to a subject. In some embodiments, the method includes administering 160 mg to 400 mg of compound A to a subject. In some embodiments, the method includes administering 200 mg to 400 mg of compound A to a subject. In some embodiments, the method includes administering 220 mg to 400 mg of compound A to a subject. In some embodiments, the method includes administering 250 mg to 400 mg of compound A to a subject. In some embodiments, the method includes administering 300 mg to 400 mg of compound A to a subject. In some embodiments, the method includes administering 350 mg to 400 mg of compound A to a subject.

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

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

[0014] 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.

[0015] In some embodiments, the method includes administering 100 mg of compound A to the subject twice daily (i.e., a total daily dose of 200 mg). In some embodiments, the method includes administering 200 mg of compound A to the subject twice daily (i.e., a total daily dose of 400 mg). In some embodiments, the method includes administering 300 mg of compound A to the subject twice daily (i.e., a total daily dose of 600 mg). In some embodiments, the method includes administering 400 mg of compound A to the subject twice daily (i.e., a total daily dose of 800 mg).

[0016] In some embodiments, the RAS protein-associated condition is cancer. In some embodiments, the cancer comprises a RAS mutation. In some embodiments, the RAS mutation is at position 12. In some embodiments, the RAS mutation is G12C. In some embodiments, the cancer comprises 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, an SHP2 inhibitor, an 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 multiselective RAS(ON) 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 KRAS. G12C Inhibitor. In some embodiments, the second RAS inhibitor is a selective RAS(ON) G12C inhibitor. In some embodiments, the second RAS inhibitor is KRAS. G12C (OFF) inhibitor.

[0017] In particular, it is considered that any limitations discussed with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention. Attached Figure Description

[0018] Figure 1 The Phase 1 study design for compound A is presented.

[0019] Figure 2 For KRAS G12C A waterfall plot of the best overall response to compound A in NSCLC subjects, with or without prior KRAS treatment. G12C(OFF) Inhibitor therapy. (1) All patients receiving treatment received their first dose of RMC-6291 at least 8 weeks prior to the data retrieval date. (2) Tumor response was assessed according to RECIST 1.1. (3) PRs included 5 confirmed PRs and 3 unconfirmed PRs. Pru = unconfirmed PR according to RECIST 1.1; G12Ci = G12C inhibitor.

[0020] Figure 3 Depicting those who have not received KRAS G12C KRAS treated with (OFF) inhibitors G12C Best overall response to compound A in CRC. 1) All treated patients received their first dose of RMC-6291 at least 8 weeks prior to the data extraction date. (2) Tumor response was assessed according to RECIST 1.1. (3) PRs included 5 confirmed PRs and 3 unconfirmed PRs. (4) One patient had a PR due to the development of a new lesion, and the target lesion could not be measured. Pru = unconfirmed PR according to RECIST 1.1.

[0021] Figure 4 The graphs show the mean plasma concentrations of compound A over time after oral administration once daily (50 mg, 100 mg, and 200 mg) or twice daily (200 mg). Subjects considered outliers have been excluded from the graphs in the 50 mg cohort. Detailed Implementation

[0022] Compound A is a RAS inhibitor, more specifically, a RAS(ON) G12C-selective, ternary complex inhibitor that is selective for the active GTP-binding state of the typical RAS isotype with G12C mutation. Compound A binds to cyclic protein A, which is highly expressed in normal tissues and tumors, to form a binary complex that covalently binds to RAS. G12C (ON) forms a ternary complex, blocking downstream RAS signal transduction (Schulze et al., Science. 2023 Aug 18; 381(6659): 794-799).

[0023] definition In this application, unless the context clearly indicates otherwise, (i) the term “a” means “one or more”; (ii) the term “or” is used to mean “and / or” unless explicitly indicated that the term refers to a unique alternative or that the alternatives are mutually exclusive; however, the definition supported by this disclosure refers to a unique alternative and “and / or”; (iii) the terms “comprising” and “including” should be understood to encompass the listed components or steps, whether presented alone or in combination with one or more additional components or steps; and (iv) when providing a scope, endpoints are included.

[0024] As used herein, the term "about" is used to indicate that a value includes the standard deviation of the error of the apparatus or method used to determine that value. In some embodiments, the term "about" refers to a range of values ​​along any direction (greater or less than) within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or lower percentages of the value, unless otherwise specified or otherwise apparent from the context (e.g., when the figure would exceed 100% of the possible value).

[0025] It should be noted that, unless otherwise indicated, when ranges or amounts are provided in the disclosure herein, each range endpoint or specific amount plus or minus 5% is included. For example, a range of 50 mg to 800 mg for compound A should be understood to cover 50 mg (+ / - 5%) to 800 mg (+ / - 5%), such as 47.5 mg to 840 mg for compound A.

[0026] As used herein, the term "administration" means administering a composition comprising compound A to a subject or system. Administration also includes administering to a subject a prodrug derivative or analogue or a pharmaceutically acceptable salt that can form an equivalent amount of the active compound in the subject's body. Administration to animal subjects (e.g., to humans) can be performed via any suitable route. For example, in some embodiments, administration can be via bronchial (including bronchial instillation), buccal, intestinal, intradermal, intraarterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intrasacral, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, surface, tracheal (including intratracheal instillation), percutaneous, vaginal, or vitreous administration. In some embodiments, the composition comprising compound A is administered orally.

[0027] The term "combination therapy" refers to a treatment method that includes administering at least two active therapeutic agents to a subject as part of a treatment regimen in the form of 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 (in single or separate composition form) or sequentially (in separate composition form). The therapeutic agents may be administered in an effective amount. The therapeutic agents may be administered in a therapeutically effective amount. In some embodiments, the effective amount of one or more therapeutic agents used in combination therapy may be lower than the therapeutic amount of the same therapeutic agent used as a monotherapy, for example, due to the additive or synergistic effect of the combination of two or more therapeutic agents.

[0028] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (e.g., compound A) intended for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, such an amount is an amount (or a portion thereof) of a unit dose suitable for administration according to a dosing regimen that is determined to be associated with a desired or beneficial outcome when administered to a relevant population (i.e., according to a therapeutic dosing regimen). Those skilled in the art will understand that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0029] As used herein, the term "dosing regimen" refers to a set of unit doses (typically more than one unit dose) administered individually to a subject, said unit doses typically spaced at intervals of time. In some embodiments, a given therapeutic compound (e.g., compound A) has a recommended dosing regimen that may involve one or more doses. In some embodiments, the dosing regimen includes multiple doses, each of which is spaced at equal intervals; in some embodiments, the dosing regimen includes multiple doses and at least two distinct time intervals separating the individual doses. In some embodiments, all doses within the dosing regimen are amounts of the same unit dose. In some embodiments, the different doses within the dosing regimen are different amounts. In some embodiments, the dosing regimen includes a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose different from that first dose. In some embodiments, the dosing regimen includes a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose identical to that first dose. In some embodiments, the dosing regimen, when administered to a relevant population, is associated with a desired or beneficial outcome (i.e., a therapeutic dosing regimen).

[0030] Unless otherwise indicated, the term “symptom” is used in this disclosure to mean the terms disease, ailment or illness, and may be used interchangeably with these terms.

[0031] The terms “inhibition,” “blocking,” and “curbing” are used interchangeably to refer to any statistically significant reduction in biological activity, including complete blockage of activity. As used herein, the term “inhibitor” refers to a compound that prevents a biomolecule (e.g., a protein, nucleic acid) from completing or initiating a reaction. Inhibitors can inhibit reactions in, for example, competitive, non-competitive, or non-competitive ways. Regarding their binding mechanism, inhibitors can be irreversible or reversible. Exemplary inhibitors include (but are not limited to) nucleic acids, DNA, RNA, shRNA, siRNA, proteins, protein mimics, peptides, peptide mimics, antibodies, small molecules, chemicals, analogs of enzyme binding sites, receptors, or other proteins. In some embodiments, the inhibitor is a small molecule, such as a low molecular weight organic compound, for example, an organic compound with 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 of the small molecule ranges from 800 Da to 1200 Da. Small molecule inhibitors include cyclic and acyclic compounds. They include natural products, their derivatives, and analogues. Small molecule inhibitors may include covalently cross-linked groups capable of forming covalent cross-links with, for example, the amino acid side chains of the target protein.

[0032] As used herein, the terms "patient" and "subject" are used interchangeably and refer to a mammal requiring diagnosis, prognosis, or therapy. 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 some embodiments, the subject has been diagnosed with cancer. In some embodiments, the subject is a person with an tumor (e.g., cancer) who has been diagnosed with a need for treatment of the tumor (e.g., cancer).

[0033] As used herein, the term "pharmaceutical composition" refers to a compound formulated with a pharmaceutically acceptable excipient, such as compound A disclosed herein, or a pharmaceutically acceptable salt thereof.

[0034] As used herein, “pharmaceuticalally acceptable excipient” means any inactive ingredient (e.g., a medium that suspends or dissolves an active compound) that is non-toxic and non-inflammatory in the body of a subject. Typical excipients include, for example: anti-adhesion agents, antioxidants, adhesives, coating agents, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavoring agents, fragrances, flow enhancers (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water for hydration. Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, croscarmellose, croscarmellose, citric acid, croscarmellose, cysteine, ethyl cellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn starch), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. A variety of agents and materials that can be used as excipients are well known to those skilled in the art. 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.

[0035] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound described herein that, to the extent reasonably medically permissible, is suitable for use in contact with tissues of humans and other animals without excessive toxicity, irritation, anaphylactic reactions, etc., and is proportionate to 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, (edited by PH Stahl and CGWermuth), Wiley VCH, 2008. The salt may be prepared in situ during the final isolation and purification of the compound described herein, or separately by reacting a free basic group with a suitable organic acid.

[0036] The term “RAS inhibitor” is used interchangeably with “[a] RAS inhibitor” and refers to any inhibitor that targets (i.e. selectively binds to or inhibits) the RAS protein.

[0037] As used herein, the terms “RAS(ON) multiselective inhibitor,” “RAS multi-inhibitor,” “RAS multi-(ON) inhibitor,” or “RAS(multi) inhibitor” refer to a RAS inhibitor of at least three RAS isotypes, including 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.

[0038] As used herein, the term "RAS(ON) mutant selective inhibitor" refers to a RAS inhibitor that is selective for a RAS(ON) variant having a missense mutation at one of the following positions: 12, 13, or 61. Non-limiting examples of RAS(ON) mutant 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.

[0039] As used herein, the term "RAS(ON) inhibitor" refers to an inhibitor that targets (i.e., selectively binds to or inhibits) the active GTP-binding state of RAS (e.g., selectively exceeding the inactive GDP-binding state of RAS). Inhibition of the active GTP-binding state of RAS includes, for example, inhibiting oncogenic signaling from the active GTP-binding state of RAS. In some embodiments, the RAS(ON) inhibitor is an inhibitor that selectively binds to and inhibits the active GTP-binding state of RAS. In some embodiments, the RAS(ON) inhibitor may also bind to or inhibit the inactive GDP-binding state of RAS (e.g., with an affinity or inhibition constant lower than that for the active GTP-binding state of RAS). In some embodiments, the RAS(ON) inhibitors used in this disclosure may form a high-affinity three-component complex or conjugate between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., RAS) and a cytosolic chaperone protein (presenting protein) (e.g., cyclophilin A) that is widely expressed in the cell. More specifically, in some implementations, the RAS inhibitors described herein induce novel binding pockets in RAS by driving the formation of a high-affinity ternary complex or conjugate between the RAS protein and the widely expressed cytosol chaperone protein cyclophilin A (CYPA).

[0040] As used herein, the term “RAS(OFF) inhibitor” refers to an inhibitor that targets (i.e. selectively binds to or inhibits) the inactive GDP binding state of RAS (e.g., selectively over the active GTP binding state of RAS).

[0041] The terms “RAS pathway” and “RAS / MAPK pathway” are used interchangeably in this document. They refer to the signal transduction cascade downstream of various cell surface growth factor receptors, in which the activation of the RAS (and its various isoforms and alloforms) is central to driving a variety of cellular effector events that determine cell proliferation, activation, differentiation, mobilization, and other functional properties. SHP2 transmits positive signals from growth factor receptors to the RAS activation / deactivation cycle, regulated by guanine nucleotide exchange factors (GEFs, such as SOS1), which load GTP onto the RAS to produce functionally active GTP-binding RAS and GTP-accelerating proteins (GAPs, such as NF1), which promote signal termination by converting GTP to GDP. The GTP-binding RAS generated by this cycle transmits the necessary positive signals to a series of serine / threonine kinases (including RAF and MAP kinases), from which additional signals are emitted for various cellular effector functions.

[0042] "Therapeutic agent" is any substance, such as a compound or composition, capable of treating a disease or condition. In some embodiments, therapeutic agents available for the purposes of this disclosure include RAS inhibitors and cancer chemotherapy agents. Many of these therapeutic agents are known in the art and disclosed herein.

[0043] The term "therapeuticly effective amount" means an amount sufficient to treat a disease, condition, or disorder when administered according to a therapeutic dosing regimen to a population suffering from or susceptible to that disease, condition, or disorder. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence or severity of one or more symptoms of the disease, condition, or disorder, or delays its onset. Those skilled in the art will understand that the term "therapeuticly effective amount" does not actually require successful treatment in a particular individual. In fact, a therapeutically effective amount can be an amount that provides a specific desired pharmacological response in a substantial number of subjects when administered to a patient requiring that treatment. It is particularly important to understand that a particular subject can actually be "therapeuticly effective" and "refractory." In some embodiments, the reference to a therapeutically effective amount may refer to an amount measured in one or more specific tissues (e.g., tissues affected by the disease, condition, or disorder) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, a therapeutically effective amount may be formulated as a single dose or administered in a single dose. In some implementations, the therapeutically effective amount may be formulated as multiple doses, for example, as part of a dosing regimen, or administered in multiple doses.

[0044] The term "treatment" (and "treat" or "treating") in its broadest sense refers to any administration of a substance (e.g., compound A) that partially or completely relieves, improves, reduces, or inhibits one or more symptoms, features, or causes of a particular disease, condition, or disorder; delays its onset; reduces its severity; or decreases its occurrence. In some embodiments, such treatment may be administered to a subject who does not exhibit signs of the relevant disease, condition, or disorder, or to a subject who exhibits only early signs of the disease, condition, or disorder. Alternatively or additionally, in some embodiments, treatment may be administered to a subject who exhibits one or more identified signs of the relevant disease, condition, or disorder. In some embodiments, treatment may be used on a subject diagnosed with the relevant disease, condition, or disorder. In some embodiments, treatment may be used on a subject known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, condition, or disorder. In any treatment method described herein, the patient or subject may require such treatment.

[0045] Treatment Generally, this disclosure is characterized by a method for treating RAS protein-related conditions (e.g., cancer) in human subjects of need, said method comprising administering (e.g., orally) 50 mg to 800 mg of compound A daily: Compound A (also known as RMC-6291 or RM-046).

[0046] Compound A may exist in conformational stereoisomers, such as transisomers. Pharmaceutically acceptable salts of compound A are also included, as well as solvates, hydrates, and polymorphs. See, for example, WO 2021 / 091982 and PCT / US2024 / 024246, which are incorporated herein by reference in their entirety. Compound A may be prepared as described in WO 2021 / 091982 and WO 2022 / 235864, each of which is incorporated herein by reference in its entirety.

[0047] Compound A may exist in a pharmaceutically acceptable isotopic form, wherein one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from those commonly found in nature. Examples of isotopes that can be incorporated into compound A include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, for example, 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O and 18 O. These radiolabeled compounds can be used to help determine or measure the effectiveness of compound A by characterizing, for example, the site of action or mode of action. Certain isotopic labeling schemes of compound A, such as those incorporating a radioisotope, can be used for drug and / or substrate tissue distribution studies. Radioisotope tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) is particularly useful for achieving this purpose because it is easy to incorporate and easy to detect.

[0048] Use heavier isotopes, such as deuterium (i.e., 2 H) substitution can offer certain therapeutic advantages due to higher metabolic stability, such as increased in vivo half-life or reduced dose requirement. Using positron-emitting isotopes (e.g.) 11 C 15 O and 13 Substitution of N) can be used for positron emission morphology (PET) studies.

[0049] A method for treating a subject with cancer is also provided, the method comprising administering to the subject a therapeutically effective amount of compound A. 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 carcinoma of the lung. In some embodiments, the cancer contains a RAS mutation, such as KRAS G12C. In some embodiments, cancer containing a KRAS G12C mutation may also contain additional RAS mutations. Other RAS mutations are described herein.

[0050] A method for treating RAS protein-related conditions in a subject in need is also provided, the method comprising administering to the subject a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments of any of the methods described herein, the method includes administering to a subject in need a total daily dose between 50 mg and 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 to 700 mg, 120 mg to 700 mg, 160 mg to 700 mg, 200 mg to 700 mg, 250 mg to 700 mg). mg, 300 mg to 700 mg, 350 mg to 700 mg, 400 mg to 700 mg, 450 mg to 700 mg, 500 mg to 700 mg, 550 mg to 700 mg, 600 mg to 700 mg, 650 mg to 700 mg, 60 mg to 600 mg, 80 mg to 600 mg, 120 mg to 600 mg, 160 mg to 600 mg, 200 mg to 600 mg, 250 mg to 600 mg, 300 mg to 600 mg, 350 mg to 600 mg, 400 mg to 600 mg, 450 mg to 600 mg, 500 mg to 600 mg, 550 mg to 600 mg, 60 mg to 500 mg, 80 mg to 500 mg, 120 mg to 500 mg, 160 mg to 500 mg, 200 mg to 500 mg mg, 220 mg to 500 mg, 250 mg to 500 mg, 300 mg to 500 mg, 350 mg to 500 mg, 400 mg to 500 mg, 450 mg to 500 mg, 60 mg to 400 mg, 80 mg to 400 mg, 120 mg to 400 mg, 160 mg to 400 mg, 200 mg to 400 mg, 250 mg to 400 mg, 300 mg to 400 mg, 350 mg to 400 mg, 50 mg to 300 mg, 60 mg to 300 mg, 80 mg to 300 mg, 120 mg to 300 mg, 160 mg to 300 mg, 200 mg to 300 mg, 250 mg to 300 mg, 50Compound A (at a total daily dose between 250 mg and 60 mg, 250 mg, 80 mg and 250 mg, 120 mg and 250 mg, 160 mg and 250 mg, 50 mg and 200 mg, 60 mg and 200 mg, 80 mg and 200 mg, 120 mg and 200 mg, 160 mg and 200 mg, 50 mg and 160 mg, 60 mg and 160 mg, 80 mg and 160 mg, 120 mg and 160 mg, 50 mg and 120 mg, 60 mg and 120 mg, 80 mg and 120 mg, 50 mg and 80 mg, 60 mg and 80 mg, 70 mg and 80 mg, 50 mg and 100 mg, 60 mg and 100 mg, or 80 mg and 100 mg). In each of the foregoing embodiments, the total daily dose may be administered once or twice daily.

[0052] In some embodiments, the method includes administering to a subject in need 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, 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, or 525 mg of a certain concentration. Compound A at a total daily dose of 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg. In each of the foregoing embodiments, the total daily dose may be administered once or twice daily.

[0053] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 300 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 400 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 450 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 500 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 550 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 600 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 650 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 700 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 750 mg to 800 mg to a subject in need.

[0054] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 300 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 400 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 450 mg to 800 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 500 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 550 mg to 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 600 mg to 800 mg to a subject in need. In some implementations, the method includes administering a total daily dose of compound A of 650 mg to 700 mg to a subject in need.

[0055] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 600 mg to a subject in need. 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 250 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 300 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 400 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 450 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 500 mg to 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 550 mg to 600 mg to a subject in need.

[0056] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 500 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 350 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 400 mg to 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 450 mg to 500 mg to a subject in need.

[0057] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 300 mg to 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to 400 mg to a subject in need.

[0058] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 300 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 300 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 300 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 300 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 300 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 300 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 300 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 200 mg to 300 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 250 mg to 300 mg to a subject in need.

[0059] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 200 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 200 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 200 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 200 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 200 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 200 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 160 mg to 200 mg to a subject in need.

[0060] 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 includes administering a total daily dose of compound A of 375 mg to 425 mg to a subject in need.

[0061] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 160 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 160 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 160 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 160 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 160 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 120 mg to 160 mg to a subject in need.

[0062] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 120 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 120 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 120 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 120 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 100 mg to 120 mg to a subject in need.

[0063] In some embodiments, the method includes administering a total daily dose of compound A of 50 mg to 100 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 60 mg to 100 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 70 mg to 100 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 80 mg to 100 mg to a subject in need.

[0064] In some embodiments, the method includes administering 50 mg of compound A to a subject in need of a total daily dose. In some embodiments, the method includes administering 60 mg of compound A to a subject in need of a total daily dose. In some embodiments, the method includes administering 70 mg of compound A to a subject in need of a total daily dose. In some embodiments, the method includes administering 80 mg of compound A to a subject in need of a total daily dose. In some embodiments, the method includes administering 100 mg of compound A to a subject in need of a total daily dose. In some embodiments, the method includes administering 120 mg of compound A to a subject in need of a total daily dose. In some embodiments, the method includes administering 160 mg of compound A to a subject in need of a total daily dose. In some embodiments, the method includes administering 200 mg of compound A to a subject in need of a total daily dose. In some embodiments, the method includes administering 250 mg of compound A to a subject in need of a total daily dose. In some embodiments, the method includes administering 300 mg of compound A to a subject in need of a total daily dose. In some embodiments, the method includes administering a total daily dose of compound A of 350 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 400 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 450 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 500 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 550 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 600 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 650 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 700 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 750 mg to a subject in need. In some embodiments, the method includes administering a total daily dose of compound A of 800 mg to a subject in need.

[0065] In several 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 several embodiments, compound A is administered in separate daily doses, such as twice, three, four, five, or six times a day.

[0066] In some embodiments of the methods disclosed herein, compound A is administered orally to the subject once daily (QD) at the dose disclosed herein.

[0067] In some embodiments of the methods disclosed herein, compound A is administered orally to the subject twice daily (BID) at the dose disclosed herein.

[0068] In some embodiments of the methods disclosed herein, compound A is administered to a subject by BID at a dose of 175 mg to 325 mg. In some embodiments, the method includes administering compound A by BID at a subject who requires it at a dose of 200 mg to 300 mg. In some embodiments, the method includes administering compound A by BID at a subject who requires it at a dose of 225 mg to 275 mg. In some embodiments, the method includes administering compound A by BID at a subject who requires it at a dose of 200 mg. In some embodiments, the method includes administering compound A by BID at a subject who requires it at a dose of 300 mg. In some embodiments, the method includes administering compound A by BID at a subject who requires it at a dose of 400 mg.

[0069] In some embodiments, the methods or uses described herein also include the administration of additional anticancer therapy. 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 multiselective RAS(ON) inhibitor), an SHP2 inhibitor, an 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.

[0070] In several embodiments, compound A is applied once, twice, three times, four times, five times, six times, or seven times per week. In several embodiments, compound A is applied seven days a week. In several embodiments, compound A is applied six days a week. For example, compound A is applied on days 1, 2, 3, 4, 5, and 6 of each seven-day period. In several embodiments, compound A is applied five days a week. For example, compound A is applied on days 1, 2, 3, 4, and 5 of each seven-day period. In several embodiments, compound A is applied four days a week. For example, compound A is applied on days 1, 2, 3, and 4 of each seven-day period. In several embodiments, compound A is applied three days a week. For example, compound A is applied on days 1, 2, and 3 of each seven-day period. In several embodiments, compound A is applied two days a week. For example, compound A is applied on days 1 and 2 of each seven-day period.

[0071] In several embodiments, compound A is administered to the subject 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 several embodiments, compound A is administered to the subject for at least 1 month. In several embodiments, compound A is administered to the subject for at least 3 months. In several embodiments, compound A is administered to the subject for at least 6 months. In several embodiments, compound A is administered to the subject for at least 8 months. In several embodiments, compound A is administered to the subject for at least 10 months. In several embodiments, compound A is administered to the subject for at least 12 months.

[0072] In some embodiments, compound A is administered in treatment cycles. 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 many embodiments, the subject experiences 1, 2, 3, 4, or more treatment cycles. In some embodiments, the subject experiences at least 3 treatment cycles, at least 5 treatment cycles, at least 8 treatment cycles, at least 10 treatment cycles, at least 15 treatment cycles, at least 20 treatment cycles, at least 25 treatment cycles, or more treatment cycles.

[0073] As is known to those skilled in the art, after a subject has taken compound A for an appropriate period of time, the response rate or outcome of a subject who has been administered compound A in the methods disclosed herein can be measured in various ways.

[0074] As determined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer et al., 2009), a subject is considered to have a response to therapy, as measured by at least stable disease (SD). RECIST v1.1 is discussed in detail in the examples below. At least stable disease is stable disease that has shown a partial response (PR) or a complete response (CR) (i.e., "at least SD" = SD + PR + CR, often referred to as disease control). In several embodiments, stable disease does not have a reduction sufficient to qualify for a partial response (PR) nor an increase sufficient to qualify for disease progression (PD). In several embodiments, the patient demonstrates at least a partial response (i.e., "at least PR" = PR + CR, often referred to as an objective response).

[0075] The response can be measured by one or more of the following: reduction in tumor size, inhibition or reduction in tumor growth, reduction in target or tumor lesions, delayed progression time, absence of new tumors or lesions, reduction in new tumor formation, increased survival or progression-free survival (PFS), and absence of metastasis. In several implementations, the progression of a patient's disease can be assessed by measuring tumor size, the presence or formation of new tumors or lesions, and by evaluating the patient using computed tomography (CT) scans, positron emission tomography (PET) scans, magnetic resonance imaging (MRI) scans, X-rays, ultrasound, or some combination thereof.

[0076] Several criteria and definitions disclosed in the literature can be used to determine the effect of one or more treatments on tumors in subjects with cancer. Based on these criteria, a tumor is defined as “responsive,” “stable,” or “progressive,” respectively, when it improves, remains unchanged, or worsens during treatment. The amount of tumor in an individual is called “tumor burden,” which can be measured as the number, volume, and / or weight of tumors.

[0077] Examples of commonly used guidelines published in the literature include the Response Evaluation Criteria in Solid Tumors (RECIST), the Modified Response Evaluation Criteria in Solid Tumors (mRECIST), the PET Response Criteria in Solid Tumors (PERCIST), the Choi criteria, the Lugano response criteria, the European Association for the Study of the Liver (EASL) criteria, the Response Evaluation Criteria in the Cancer of the Liver (RECICL), and the WHO Tumor Response Criteria.

[0078] As used herein, “progression-free survival” or “PFS” is the time from treatment to the date of first confirmed disease progression, according to RECIST 1.1 guidelines. In several implementations, patients demonstrate at least 1 month of PFS. In several implementations, patients demonstrate at least 3 months of PFS. In some implementations, patients demonstrate at least 6 months of PFS.

[0079] "RECIST" is an acronym for "Responsiveness Assessment Criteria for Solid Tumors," a set of published rules defining when a cancer patient's condition improves ("response"), remains unchanged ("stable"), or worsens ("progression") during treatment. Responses defined by RECIST criteria are published, for example, in the Journal of the National Cancer Institute, Volume 92, Issue 3, February 2, 2000, and RECIST criteria may include other sets of similar published definitions and rules. Those skilled in the art will understand that definitions conforming to RECIST criteria as used herein include, for example, "partial response (PR)," "complete response (CR)," "stable disease (SD)," and "progressive disease (PD)."

[0080] As used in this article, “survival” means that the subject remains alive and includes overall survival and progression-free survival.

[0081] As used herein, “reducing tumor size” 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 some embodiments, the metastases are skin or subcutaneous. Thus, in some embodiments, such as relative to a control drug in a subject with the same genotype, administration of an immune checkpoint inhibitor reduces the size or volume of the tumor 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%. In some embodiments, such as relative to a control drug in a subject with the same genotype, administration of compound A or a combination therapy comprising it reduces the weight of the tumor 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%. In some embodiments, such as relative to a control drug in a subject with the same genotype, administration of compound A or a combination therapy comprising it reduces the size or volume of metastases 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%. In some embodiments, such as relative to a control drug in a subject with the same genotype, administration of a RAS(ON) inhibitor therapy or a combination therapy comprising it reduces the number of metastases 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%. In some embodiments, combinations achieve these effects.

[0082] 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. Biological samples may be obtained from a subject before or after diagnosis, at one or more time points before or after treatment or therapy, at one or more time points during which no treatment or therapy is available, or may be collected from a healthy subject. Biological samples may be tissue samples or fluid samples. In some embodiments, biological samples include tissue samples, biopsy samples, tumor aspirates, bone marrow aspirates, or blood samples (or portions thereof, such as blood or serum). In some embodiments, biological samples include tumor cells or cancer cells, such as circulating tumor cells present in a fluid sample (e.g., blood or a portion thereof). In some embodiments, biological samples include cell-free nucleic acids present in a fluid sample (e.g., blood or a portion thereof). In one embodiment, the biological sample comprises a cell lysis product (or a portion of the lysis product) or a cell extract; or a solution containing one or more molecules derived from cells or cellular material (e.g., peptides or nucleic acids). Cell lysis products may include protein, nuclear, and / or mitochondrial portions. In some embodiments, cell lysis products include cytosolic portions. In some embodiments, the cell lysis products include nuclear / mitochondrial fractions and cytosol fractions.

[0083] Biological samples can be derived from fresh, frozen, and / or preserved organ, tissue, biopsy, or aspirate samples; solid tissue; blood or any blood component; body fluids such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; or cells from any stage of pregnancy or development in the subject. Biological samples may contain compounds that do not naturally mix with tissues in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, etc. Biological samples may be preserved as frozen samples or formaldehyde or paraformaldehyde-fixed paraffin-embedded (FFPE) tissue preparations. For example, the sample may be embedded in a matrix such as an FFPE block or a frozen sample. However, other tissue and sample types are applicable herein. In one embodiment, other tissue and sample types may be fresh frozen tissue, washes, or cell clumps, etc. Biological samples may be tumor samples containing nucleic acid molecules from a tumor or cancer. A biological sample is a tumor sample, which 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., removed from its native state). In one implementation, the sample is tissue (e.g., tumor biopsy), CTC, or cell-free nucleic acid.

[0084] In some embodiments, tumor samples are isolated from human subjects. In some embodiments, tumor biopsies embedded in paraffin are analyzed. In one embodiment, the sample may be a fresh frozen tissue sample. In some embodiments, the sample is a bodily fluid obtained from a subject. The bodily fluid may be blood or a portion thereof (specifically, serum, plasma), urine, saliva, sputum, or cerebrospinal fluid (CSF). The sample may contain cells as well as nucleic acids of extracellular origin. The extracellular origin may be cell-free nucleic acids and / or exosomes. The methods described herein (including RT-PCR methods) are sensitive, accurate, and multianalyte-capable for use with paraffin-embedded samples. See, for example, Cronin et al., Am. J Pathol. 164(1):35-42 (2004).

[0085] Additional means for evaluating the reaction are described in detail in the examples below and are generally applicable to the methods disclosed herein.

[0086] In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject an amount of compound A as described herein. Therefore, one embodiment of this disclosure provides a method of treating a subject in need by administering a pharmaceutical composition containing an amount of compound A as described herein and a pharmaceutically acceptable excipient, and a method of preparing such a composition using compound A.

[0087] In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including forms suitable for: oral administration, such as drenching (aqueous or non-aqueous solutions or suspensions), tablets (e.g., tablets intended for absorption via the buccal, sublingual, and systemic routes), pellets, powders, granules, or pastes for application to the tongue; parenteral administration, such as via subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions, or sustained-release formulations; topical administration, such as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or mouth; intravaginal or rectal administration, such as pessaries, creams, or foams; sublingual; ocular; transdermal; or via the nose, lungs, and other mucosal surfaces.

[0088] For use as a treatment for subjects, compound A can be formulated as a pharmaceutical composition. Depending on the subjects to be treated, the mode of administration, and the type of treatment required, such as prevention, treatment, or therapy, compound A is formulated in a manner consistent with these parameters. A summary of such techniques can be found in [link to relevant documentation]. Remington: The Science and Practice of Pharmacy, No. 21 version Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceuticals TechnologyJ. Swarbrick and JC Boylan, eds., 1988–1999, Marcel Dekker, New York, each incorporated herein by reference.

[0089] The compositions can be prepared according to conventional mixing, granulation, or coating methods, and the pharmaceutical compositions of the present invention may contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of compound A by weight or volume. In some embodiments, compound A may be present in an amount totaling 1% to 95% by weight of the total weight of the composition (e.g., the pharmaceutical composition).

[0090] The composition may be provided in dosage forms suitable for administration as follows: intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, skin, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intracystic, intraurethral, ​​intrathecal, epidural, ocular, or by injection, inhalation, or direct contact with the mucous membranes of the nose, genitourinary tract, genitals, or mouth. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, solutions, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, formulations suitable for iontophoresis delivery, or aerosols. The composition may be formulated according to conventional pharmaceutical practice.

[0091] Formulations can be prepared in a manner suitable for systemic or topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or those prepared for transdermal, transmucosal, or oral administration. Formulations will generally include diluents, and in some cases, adjuvants, buffers, preservatives, etc. Compounds or pharmaceutically acceptable salts thereof may also be administered in liposome compositions or as microemulsions.

[0092] For injection, the formulation can be prepared in conventional forms, such as liquid solutions or suspensions, or in solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or as emulsions. Suitable excipients include, for example, water, physiological saline, dextrose, glycerol, etc. These compositions may also contain a certain amount of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitol monolaurate, etc.

[0093] Various sustained-release drug delivery systems have also been designed. See, for example, U.S. Patent No. 5,624,677.

[0094] Systemic administration may also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or pharmaceutically acceptable salts thereof. It will be understood in the art that suitable forms include syrups, capsules, and tablets. In one embodiment, a therapeutically effective amount of compound A is administered orally in the form of tablets or multiple tablets.

[0095] Compound A, as described herein, can be formulated in a variety of ways known in the art. For example, the first and second doses in a combination therapy can be formulated together or separately. Other modalities of combination therapy are described herein.

[0096] Individually or separately formulated preparations may be packaged together in a pillbox form. Non-limiting examples include, but are not limited to, pillboxes containing, for example, two pills, one pill and powder, suppositories and liquid in a vial, two topical creams, etc. The pillbox may include optional components to facilitate the administration of a unit dose to a subject, such as vials for reconstitution of the powder form, syringes, custom IV delivery systems, inhalers, etc. Additionally, the unit-dose pillbox may contain instructions regarding the preparation and administration of the composition. The pillbox may be manufactured as a single-use unit dose for one subject, for multiple uses for a specific subject (at a constant dose, or where the potency of a single compound or its pharmaceutically acceptable salt may vary with treatment progression); or the pillbox may contain multiple doses suitable for administration to multiple subjects (“integral package”). Pillbox components may be assembled in cartons, blister packs, bottles, tubes, etc.

[0097] Oral formulations include tablets containing a mixture of an active ingredient and a non-toxic, pharmaceutically acceptable excipient. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives, including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginate, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, 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, humectants, buffers, etc.

[0098] Two or more compounds may be mixed together in tablets, capsules, or other media, or they may be separated. In one example, the first compound is contained on the inside of the tablet, and the second compound on the outside, thereby releasing the majority of the second compound before the first compound is released.

[0099] Oral formulations may also be provided in chewable tablet form, or in hard gelatin capsule form, wherein compound A is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin); or in soft gelatin capsule form, wherein compound A is mixed with an aqueous or oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and fine pellets may be prepared using the ingredients mentioned above for tablets and capsules, in a conventional manner, using, for example, a mixer, a fluid bed apparatus, or a spray drying device.

[0100] Controlled release through dissolution or diffusion can be achieved by appropriately coating the compound with tablets, capsules, fine granules, or granules, or by incorporating compound A into a suitable matrix. Controlled release coatings may include one or more of the coating substances mentioned above, or for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethacrylate, methacrylate hydrogel, 1,3-butanediol, ethylene glycol methacrylate, or polyethylene glycol. In controlled-release matrix formulations, matrix materials 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.

[0101] Liquid forms of compounds A or their compositions that can be incorporated into the oral administration include aqueous solutions, appropriately 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 mediators.

[0102] In some embodiments, the pharmaceutical composition may also contain additional compounds having antiproliferative activity. Depending on the administration regimen, the compounds or pharmaceutically acceptable salts thereof will be formulated into suitable compositions for easy delivery. Each compound or pharmaceutically acceptable salt thereof in the combination therapy may be formulated in a variety of ways known in the art. For example, the first and second doses in the combination therapy may be formulated together or separately. Ideally, the first and second doses are formulated together for simultaneous or near-simultaneous administration of the agents.

[0103] It should be understood that compound A and its pharmaceutical compositions may be formulated and used in combination therapies, i.e., compound A and its pharmaceutical compositions may be formulated together with one or more other desired therapeutic agents or medical procedures, or administered concurrently with, before, or after the administration of such one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutic agents or procedures) used in a combination regimen should take into account the compatibility of the desired therapeutic agents or procedures with the desired therapeutic effect to be achieved. It will also be understood that the therapies used may achieve the desired effect against the same condition, or they may achieve different effects (e.g., controlling any adverse effects).

[0104] As described in this article, each drug in the combination therapy can be administered independently, one to four times daily, for one day to one year, or even for the subject's lifetime. Long-term, chronic administration can be indicated.

[0105] In some embodiments, this disclosure provides a method for treating a disease or condition characterized by abnormal RAS activity caused by a RAS G12C mutation. In some embodiments, the disease or condition is cancer.

[0106] Therefore, this disclosure provides a method for treating cancer in a subject of need, the method comprising administering to the subject an amount of compound A as disclosed herein or a pharmaceutical composition comprising such a compound. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendix cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary site, endometrial cancer, esophageal and gastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendix cancer, endometrial cancer, or melanoma. A method for treating RAS protein-related conditions in a subject of need is also provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0107] As used herein, the terms “cancer” or “tumor” refer to cells that exhibit the typical characteristics of cancerous cells (such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rates, and certain characteristic morphological features). Cancer cells typically take the form of tumors, but these cells can exist alone in an animal or can be non-tumorigenic, such as leukemia cells. Cancers include (but are not limited to) B-cell malignancies, such as multiple myeloma; heavy chain diseases, such as alpha chain disease, gamma chain disease, and μ chain disease; benign monoclonal gammopathy; and immune cell amyloidosis, skin cancer, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, pancreatic cancer, stomach cancer, ovarian cancer, bladder cancer, brain cancer 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, bile duct cancer, small intestine or appendix cancer, salivary gland cancer, thyroid cancer, adrenal cancer, osteosarcoma, chondrosarcoma, and blood tissue cancers. Other non-limiting examples of cancer types suitable for the methods covered in this disclosure include human sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, 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, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, liver cancer, choriocarcinoma, seminoma, embryonal carcinoma, and Wilms' tumor. Cancers include: cervical cancer, bone cancer, brain tumors, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias such as acute lymphoblastic leukemia and acute myeloid leukemia (myeloblastic leukemia, promyelocytic leukemia, granulocytic leukemia, monocytic leukemia, and erythroleukemia); chronic leukemias (chronic myeloid (granulocytic) leukemia and chronic lymphocytic leukemia); as well as polycythemia vera, lymphomas (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease. In some implementations, the cancer is an epithelial cancer, such as, 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 implementations, the cancer is breast cancer, prostate cancer, lung cancer, or colon cancer.In other implementations, the epithelial carcinoma is non-small cell lung cancer, non-papillary renal cell carcinoma, cervical cancer, ovarian cancer (e.g., serous ovarian carcinoma), or breast cancer.

[0108] In some embodiments, compound A, pharmaceutical compositions comprising compound A or its salts, and the methods provided herein can be used to treat a wide range of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, treatable cancers and the methods of this disclosure include, but are not limited to, tumor types such as: astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma. Other cancers include, for example: Cardiac cancers, such as: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung cancer, such as: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancers, such as: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, islet tumor, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), and colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Urogenital tract cancers, such as: kidney cancer (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminomatous seminoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma); Liver cancer, such as: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer, such as gallbladder cancer, ampullary cancer, and bile duct cancer; Bone cancers, such as: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrogenic exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; Cancers of the nervous system, such as: skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma; Gynecological cancers, such as: uterine cancer (endometrial cancer, uterine cancer, endometrial cancer), cervical cancer (cervical cancer, pretumoral cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube cancer); Cancers of the hematopoietic system, such as: blood cancers (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders (such as myelofibrosis and myeloproliferative neoplasms, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin cancers, such as: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal carcinoma, for example: neuroblastoma.

[0109] In some embodiments, the cancer contains a RAS mutation, such as the RAS mutation described herein. In some embodiments, the cancer contains 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 mutants: 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 mutants: 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; and (c) The following NRAS mutants: 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 aforementioned mutations. 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 combinations 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.

[0110] In some embodiments, the cancer contains an NRAS G12C mutation. In some embodiments, the cancer contains an HRASG12C mutation. In some embodiments, the cancer contains both NRAS G12C and KRAS G12C mutations.

[0111] Methods for detecting RAS mutations are known in this art. These methods include (but are not limited to) direct sequencing and methods utilizing highly sensitive diagnostic assays (with CE-IVD markers), such as those described in Domagala et al., Pol J Pathol 3: 145-164 (2012) (which is incorporated herein by reference in its entirety), including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See also, for example, WO 2020 / 106640.

[0112] In some implementations, the cancer includes RAS mutations and STK11. LOF KEAP1, EPHA5, or NF1 mutations, or combinations thereof. In some embodiments, the cancer is non-small cell lung cancer and contains a KRAS G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and contains a KRAS G12C mutation, STK11... LOF Mutations and KEAP1 mutations. In some implementations, the cancer is non-small cell lung cancer and contains KRAS G12C and STK11 mutations. LOF Mutations. In some implementations, the cancer is non-small cell lung cancer and contains KRAS G12C and STK11 mutations. LOF Mutation. In some embodiments, the cancer is colorectal cancer and contains a KRAS G12C mutation. In some embodiments, the cancer is pancreatic cancer and contains a KRAS G12C mutation. In some embodiments, the cancer is endometrial cancer and contains a KRAS G12C mutation. In some embodiments, the cancer is gastric cancer and contains a KRAS G12C mutation.

[0113] In some embodiments, the subject treated with compound A in the disclosed method is a subject who has previously undergone at least one or more systemic cancer therapies (e.g., compound A is a second- or third-line therapy). In some embodiments, the subject treated with compound A in the disclosed method is a subject whose disease has progressed after at least one prior systemic cancer therapy (i.e., compound A is a second-line therapy). In some embodiments, the subject treated with compound A in the disclosed method is a subject whose disease has progressed after at least two prior systemic cancer therapies (i.e., compound A is a third-line therapy). The prior systemic cancer therapy can be any therapy approved by a regulatory agency (e.g., the FDA or EMA) as a treatment given according to the type and stage of cancer. In some cases, the prior systemic cancer therapy is a cancer therapy that has not yet been approved by a regulatory agency but is currently undergoing clinical trials. If the subject has previously received a systemic cancer therapy, in some cases, the subject has not experienced 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 starting treatment with compound A as disclosed herein.

[0114] In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject a composition comprising 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 to or unresponsive to treatment. In several embodiments, the subject has one or more tumors that are resistant to or unresponsive to one or more treatments selected from the group consisting of: surgery, radiation, chemotherapy, biologics, small molecules, cell-based therapies, hormone therapy, and immunotherapy. In several embodiments, the treatment is standard of care, first-line therapy, second-line therapy, or third-line therapy. In several embodiments, the subject has one or more tumors that have progressed during one or more treatments, wherein the treatment is standard of care, first-line therapy, second-line therapy, or third-line therapy.

[0115] First-line therapy is defined as treatment administered to a subject with cancer who has not received any prior treatment. Second-line therapy is defined as treatment administered to a subject with cancer who has received prior first-line therapy but experienced disease progression during that therapy. Third-line therapy is defined as treatment administered to a subject with cancer who has received prior first- and second-line therapy but experienced disease progression during that second-line therapy. Each specific type of cancer has first-, second-, and third-line therapies. First-, second-, and third-line therapies for specific cancer types are known in the art. Additionally, FDA-approved drug labeling indicates whether a particular drug is approved as a first-, second-, or third-line therapy.

[0116] In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject a composition comprising a combination of compounds A disclosed herein or a combination of compounds described herein, wherein the subject cannot tolerate standard care, first-line therapy, second-line therapy, or third-line therapy. In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject compound A or a combination therapy comprising compound A, wherein the subject has experienced tumor recurrence following surgical removal of a primary tumor. In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject a composition comprising a combination of compounds A disclosed herein or a combination of compounds described herein, wherein the subject has a tumor that cannot be surgically removed. In several embodiments, this disclosure provides a method of treating a subject with cancer, the method comprising administering to the subject a composition comprising a combination of compounds A disclosed herein or a combination of compounds described herein, wherein the subject has no available treatment options.

[0117] In some implementations, the cancer includes RAS mutations and the cancer is resistant to treatment using RAS(OFF), such as KRAS(OFF) inhibitors, such as KRASG12C(OFF) inhibitors. As used herein, the term "treatment resistance" refers to a condition treated with a therapeutic agent where the agent is ineffective, or where the agent was previously effective but has become less effective over time. Treatment resistance includes acquired and / or adaptive resistance to treatment, which refers to a decrease in therapeutic efficacy over the period during which the therapeutic agent is administered to the subject. Acquired resistance to treatment may be caused by mutations in the acquired target protein that render the treatment ineffective or less effective. Therefore, resistance to treatment may persist even after the administration of the therapeutic agent is discontinued. Specifically, cancer may be resistant to treatment using RAS(OFF) inhibitors, which reduces the efficacy of the RAS(OFF) inhibitors. Measurements of reduced therapeutic efficacy will depend on the condition being treated, and such methods are known to those skilled in the art. For example, the efficacy of cancer treatment can be measured by disease progression. Effective treatment slows or stops disease progression. Cancers resistant to treatments such as RAS(OFF) inhibitors may not slow or stop the progression of the disease.

[0118] In some embodiments, a dose of compound A may optionally be administered to the subject with food (e.g., a standardized high-fat, high-calorie diet) or in a fasting state (no food or liquids other than water, >10 hours). In one embodiment, a dose of compound A may be administered with or without food.

[0119] Monitoring for adverse events (AEs) in subjects receiving treatment is essential during the therapy process. Treatment-related AEs are those related to the treatment drug. Treatment-initiated AEs are those that were not present in the subject before treatment began but become apparent after treatment. In some cases, treatment-initiated AEs may be unrelated to or suspected to be unrelated to the treatment itself. AEs are characterized by one of five grades: Grade 1 for mild AEs; Grade 2 for moderate AEs; Grade 3 for severe AEs; Grade 4 for life-threatening or disabling AEs; and Grade 5 for AE-related death. In some cases, subjects do not exhibit any treatment-related Grade 3 AEs. In some cases, subjects do not exhibit any Grade 3 AEs. In some cases, subjects do not exhibit any treatment-related Grade 4 AEs. In some cases, subjects do not exhibit any Grade 4 AEs. In all cases, subjects do not exhibit any treatment-related Grade 3 or 4 AEs at least one month or at least three months after administration of compound A.

[0120] In all cases, subjects treated with compound A in the methods disclosed herein did not exhibit any dose-limiting toxicity (DLT) at the administered dose. DLT is any adverse events (AEs) occurring during the first treatment cycle of compound A (day 1 to day 21) that meet the criteria listed below, where a drug-related relationship cannot be ruled out.

[0121] In all cases, subjects using the disclosed methods demonstrated a response to the therapy. In some cases, subjects demonstrated at least a stable disease (SD) due to administration of compound A. In some cases, subjects demonstrated at least a partial response (PR) due to administration of compound A. Subject responses were assessed according to the criteria defined in RECIST 1.1, e.g., as discussed in Eisenhauer et al., Eur J Cancer, 45:228-247 (2009). A complete response (CR) is the disappearance of all target lesions and a reduction in the short axis of any pathological lymph nodes to less than 10 mm. A partial response (PR) is a reduction in the total diameter of target lesions of at least 30% with reference to the baseline sum of diameters. Disease progression is an increase in the total diameter of target lesions of at least 20% with reference to the minimum sum in the study (including the baseline sum if it is the minimum in the study), and an absolute increase of at least 5 mm in addition to a 20% relative increase. Stable disease does not have a reduction sufficient to qualify for PR, nor an increase sufficient to qualify for PD. A controlled disease state refers to a patient's ability to alternate between exhibiting stable disease and partial response. Tumor size can be measured using radiographic scans.

[0122] In some embodiments, the method includes monitoring modulated cardiac activity or function, such as increased QTc interval prolongation, during the course of treatment as disclosed herein. Additionally, in specific embodiments, subjects may be screened for modulated cardiac activity or function prior to implementation of the treatment disclosed herein. Examples of non-limiting methods suitable for screening or monitoring modulated cardiac activity or function in the methods of this disclosure include electrocardiography (ECG), monitoring electrolyte levels, echocardiography, stress testing, MRI, and any other examination techniques known in the art.

[0123] In various cases, the disclosed methods exclude subjects with congenital long QT syndrome or those with concurrent QTc prolongation. In some embodiments, the methods include, as clinically indicated, monitoring cardiac activity or function in subjects with (to name a non-limiting example) bradycardia, electrolyte abnormalities, or unavoidable concomitant use of medications known to prolong the QT interval, before administration, during concomitant medication use, and / or during treatment with the therapies disclosed herein. In some implementation schemes, subjects did not have cardiac abnormalities, such as 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 ≥ grade 2 as defined by the New York Heart Association, acute coronary syndrome (including unstable angina, coronary stenting or angioplasty, or bypass surgery within the past 6 months); myocardial infarction within the past 6 months; a history or evidence of currently uncontrolled, clinically significant, unstable arrhythmias; a history of congenital long QT syndrome or a corrected QT interval (QTc) prolongation > 470 ms using Fridricia's formula (unless a pacemaker is implanted); uncorrectable abnormalities in serum electrolytes (i.e., sodium, potassium, calcium, magnesium, and phosphorus); or a baseline left ventricular ejection fraction (LVEF) < 50%. Typically, the average of three readings can be used to assess the QTc interval.

[0124] In some embodiments, the method includes administering the disclosed therapy to a subject who has discontinued or avoided concomitant use of products known to prolong the QTc interval. In some embodiments, the subject may need to use drugs known to prolong the QTc interval, including but not limited to amiodarone, anagrelide, arsenic trioxide, azithromycin, chloroquine, chlorpromazine, cilostazol, ciprofloxacin, citalopram, disopyramide, dofetilide, donepezil, dronedarone, droperidol, erythromycin, and escitalopram. alopram, flecainide, fluconazole, haloperidol, ibutilide, levofloxacin, methadone, moxifloxacin, ondansetron, oxaliplatin, pentamidine, pimozide, procainamide, propofol, quinidine, sevoflurane, sotalol, thioridazine, and vandetanib.

[0125] In one aspect, this disclosure provides a method for treating a subject with cancer (e.g., cancer containing a KRAS G12C mutation), wherein the method generally includes: administering to the subject a composition comprising about 200 mg to about 400 mg of compound A, wherein the composition is administered to the subject twice daily; and monitoring the subject for QTc interval prolongation. In various cases where a change in QTc interval is detected, for example, when the absolute value of QTc is greater than 500 ms or when an increase in QTc interval from baseline is detected exceeding 60 ms, the method further includes pausing the administration of the composition containing compound A for a period sufficient to allow the QTc interval to be less than about 481 ms or to return to baseline. In some embodiments, in cases where the subject has a treatment-related QTc prolongation, the method may include reducing the dose of compound A to the next lower dose level. As a non-limiting example, a subject receiving about 300 mg of compound A twice daily could reduce the dose to about 250 mg of compound A twice daily. As another non-limiting example, a subject receiving approximately 250 mg of compound A twice daily could reduce the dose to approximately 200 mg of compound A twice daily. As another non-limiting example, a subject receiving approximately 200 mg of compound A twice daily could reduce the dose to approximately 150 mg of compound A twice daily. As yet another non-limiting example, a subject receiving between approximately 200 mg and approximately 300 mg of compound A twice daily could reduce the dose to approximately 200 mg to approximately 400 mg of compound A once daily.

[0126] In one aspect, this disclosure provides a method of treating a subject with cancer (e.g., cancer containing a KRAS G12C mutation), wherein the method generally includes administering to the subject a composition comprising an amount of compound A disclosed herein. In some embodiments, the dose of compound A disclosed herein may optionally be administered to the subject with food (e.g., a standardized high-fat, high-calorie diet) or in a fasting state (no food or liquids other than water for more than 10 hours). In one embodiment, the dose of compound A may be administered with or without food. In some embodiments, the dose of compound A is not administered with food. In some embodiments, food is not permitted for at least 4 hours after administration. In some embodiments, food is not permitted for at least 8 hours before administration. In some embodiments, food is not permitted for at least 8 hours before administration and for at least 4 hours after administration. In some embodiments, water is permitted only 1 hour before and / or 1 hour after administration.

[0127] Combination therapy This document provides compositions comprising compound A and one or more therapeutic agents for the treatment of RAS-related diseases or conditions (e.g., cancer). In some embodiments, the compositions disclosed herein comprise two or more RAS(ON) inhibitor therapies (e.g., compound A plus RMC-6236). In some embodiments, the compositions disclosed herein comprise the amount of RAS(ON) inhibitor therapy disclosed herein and one additional therapeutic agent. In some embodiments, the compositions disclosed herein comprise RAS(ON) inhibitor therapy and two additional therapeutic agents. In some embodiments, the compositions disclosed herein comprise RAS(ON) inhibitor therapy and three additional therapeutic agents. In some embodiments, the compositions disclosed herein comprise RAS(ON) inhibitor therapy and four or more additional therapeutic agents.

[0128] Pharmaceutical compositions are also provided, comprising the said combination or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Compositions comprising therapeutic combinations can be used in methods of modulating RAS (e.g., in a subject or in cells) and methods of treating RAS-related diseases and conditions (e.g., cancer), as described herein. This disclosure particularly provides compositions, methods, and kits for treating or preventing RAS-related diseases or conditions.

[0129] Compound A, as disclosed herein, may be administered before, after, or simultaneously with one or more of these additional therapies. When combined, the dosage of Compound A and the one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) given in the amounts disclosed herein provides a therapeutic effect (e.g., synergistic or additive therapeutic effect). Compound A and additional therapeutic agents, such as any of the additional therapeutic agents disclosed herein, may be administered together, for example, as a single pharmaceutical composition, or separately, and when administered separately, the administration may occur simultaneously or sequentially. Such sequential administration may be close or distant in time.

[0130] All references in this article are incorporated herein by reference for the agents described, including the compounds or molecular structures disclosed therein, whether or not so explicitly stated.

[0131] a) RAS(ON) inhibitors The compositions and methods disclosed herein include compound A plus a RAS(ON) inhibitor. In some embodiments, the RAS(ON) inhibitor is a multiselective RAS(ON) inhibitor (e.g., RMC-6236, RMC-7977, RM-034, GFH547, ERAS-0015 or compound 6A of WO 2024 / 067857). Exemplary RAS(ON) multiselective inhibitors that can be used in combinations according to this disclosure are found in any of the following patent applications: WO 2024153208, WO 2024149214, WO2024104364, WO 2024067857, WO 2024060966, WO 2024017859, WO 2024008834, WO2023240263, WO 2023025832, WO 2022060836, WO 2021091956, CN 117720556, CN117720555, CN 117720554, CN 117534687, CN 117534685 and CN 117534684, each of which is incorporated herein by reference in its entirety, including the structures of the compounds disclosed therein.

[0132] In some implementations, the RAS(ON) multiselective inhibitor is RMC-6236. (Jiang et al., Canc Discov 14:1-24 (2024)).

[0133] In some implementations, the multiselective inhibitor of RAS(ON) is compound 6A of WO 2024 / 067857: .

[0134] Some embodiments of combinations comprising RAS(ON) therapy include compositions comprising a RAS(ON) mutant-selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12D selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G13C selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) Q61H selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G12V selective inhibitor. In some embodiments, the RAS(ON) mutant-selective inhibitor is a RAS(ON) G13D selective inhibitor. Selective inhibitors of RAS(ON) mutants available according to the methods of this disclosure are found in any of the following patent applications: WO 2024102421, WO2023240263, WO 2023133543, WO 2023015559, WO 2023086341, WO 2023208005, WO2023060253, WO 2022235870, WO 2022235864, WO 2021091967, WO 2021091982, WO2021108683, WO Patent applications 2020132597, PCT / US2024 / 023208, PCT / US2024 / 023272 and PCT / US2024 / 030993, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein.

[0135] In some embodiments, the RAS(ON) mutant selective inhibitor available according to this disclosure is RMC-9805. .

[0136] In some implementations, combination therapies containing compound A may include one or more RAS(ON) inhibitors, such as compound A plus one or more RAS(ON) multiselective inhibitors and / or one or more RAS(ON) mutant selective inhibitors.

[0137] As those skilled in the art will understand, the synthesis of RAS(ON) inhibitors and known synthetic methods or variations thereof in synthetic organic chemistry techniques are known, for example, WO 2024008610, WO 2024102421, WO2023240263, WO 2023133543, WO 2023015559, WO 2023086341, WO 2023208005, WO2023232776, WO 2023060253, WO 2022235870, WO 2022235864, WO 2021091967, WO2021091982, WO 2021108683, WO As described in 2020132597, International Patent Applications No. PCT / US2024 / 023208, PCT / US2024 / 023272 and PCT / US2024 / 030993.

[0138] b) RAS / MAPK inhibitors The compositions and methods described herein may include combinations of compound A with one or more RAS / MAPK pathway inhibitors. The RAS / MAPK pathway is a signal transduction cascade downstream of various cell surface growth factor receptors, where activation of the RAS (and its various isoforms and alloforms) is central to driving a variety of cellular effector events that determine cell proliferation, activation, differentiation, mobilization, and other functional properties. SHP2 transmits positive signals from growth factor receptors to the RAS activation / deactivation cycle, regulated by guanine nucleotide exchange factors (GEFs, such as SOS1), which load GTP onto the RAS to produce functionally active GTP-binding RAS and GTP-accelerating proteins (GAPs, such as NF1), which promote signal termination by converting GTP to GDP. The GTP-binding RAS generated by this cycle transmits the necessary positive signals to a series of serine / threonine kinases (including RAF and MAP kinases), from which additional signals are emitted for various cellular effector functions. In some implementations, the therapeutic agent that can be combined with the RAS(ON) inhibitor is an inhibitor of the MAP kinase (MAPK) pathway (or "MAPK pathway inhibitor"). MAPK pathway inhibitors include, but are not limited to, one or more MAPK pathway inhibitors described in Cancer (Basel) Sep 2015;7(3):1758-1784. For example, MAPK inhibitors may be selected from one or more of the following: trametinib, binimetinib, selumetinib, cobimetinib, LERAFAON (NeoPharm), ISIS 5132; vemurafenib, pimaertib, 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, described in PLoS One. 25 November 2014; 9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 1 March 2011; 17(5): 989-1000). MAPK pathway inhibitors may be PLX8394, LXH254, GDC-5573 or LY3009120.MAPK pathway inhibitors can be PI3Kα:RAS disruptors, such as BBO-10203.

[0139] i) RAS(OFF) inhibitors and RAS(OFF) degraders The compositions and methods described herein may include combinations of compound A with one or more RAS(OFF) inhibitors. Various mutant-sensitive 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 different regions of the RAS protein in an inactive (GDP-bound) state, thereby preventing its activation and downstream signaling.

[0140] In some embodiments, the RAS(OFF) inhibitor is a KRAS(OFF) inhibitor with a molecular weight of less than 700 Da. The term "KRAS(OFF) inhibitor" refers to any RAS(OFF) inhibitor that binds to KRAS at the GDP-binding "off" position. In some embodiments, the KRAS(OFF) inhibitor is... KRAS G12C Mutations are specific. KRAS G12C (OFF) Inhibitors use a covalently bound group that allows the inhibitor to selectively target KRAS. G12C Mutant proteins, and many of these inhibitors contain a pyrimidine core. KRAS G12C (OFF) inhibitors all target KRAS. G12C The same cysteine ​​residue in the mutant protein causes a conformational change, locking the protein into an inactive state. KRAS G12C(OFF) Inhibitors include, but are not limited to, AMG510 (sottorazib), MRTX849 (adagrasisib), MRTX1257, GDC-6036 (divarasib), JDQ443 (opnurasib), ERAS-3490, LY3537982 (olomorasib), BI1823911, BPI-421286, JAB-3312, JAB-21000, JAB-21822 (glecirasib), D-1553 (garsorasib), D3S-001, HYP-209PTSA, HBI-2438, HS-10370, MK-1084, YL-15293, and 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.

[0141] In some implementations, KRAS(OFF) inhibitors are effective against... KRAS G12D Mutations are specific. Using RAS G12C Starting with (OFF) inhibitors, many KRAS inhibitors have been developed. G12D (OFF) inhibitors, therefore sharing the same G12C inhibitor skeleton, combine with other chemical motifs (e.g., piperazine-based compounds). KRAS G12D Non-limiting 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.

[0142] In some implementations, small molecule RAS(OFF) inhibitors... KRAS G12VMutations are specific. In some implementations, small molecule RAS(OFF) inhibitors target... KRAS G13D The mutation is specific. In some implementations, the small molecule RAS(OFF) inhibitor is a pan-KRAS(OFF) inhibitor.

[0143] In the current implementation plan, the following RAS(OFF) suppression is proposed. 2024138052, WO2024131829, WO 2024125642, WO 2024125600, WO 2024123913, WO 2024123102, WO2024120433, WO 2024120419, WO 2024123913, WO 2024085661,WO 2024083258, WO2024083256, WO 2024083246, WO 2024083168, WO 2024078555, WO 2024076674, WO2024076672, WO 2024076670, WO 2024067714, WO 2024067575, WO 2024064335, WO2024063578, WO 2024063576, WO 2024061370, WO 2024061333, WO 2024061267, WO2024056063, WO 2024055112, WO 2024054926, WO 2024054647, WO 2024054625, WO2024051763, WO 2024051721, WO 2024050742, WO 2024050640, WO 2024046406, WO2024046370, WO 2024045066, WO 2024044667, WO 2024044649, WO 2024044334, WO2024041621, WO 2024041606, WO 2024041589, WO 2024041573, WO 2024040131, WO2024040109, WO 2024040080, WO 2024036270, WO 2024034657, WO 2024034593, WO2024034591, WO 2024034123, WO 2024032747, WO 2024032704, WO 2024032703, WO2024032702, WO 2024031088, WO 2024030647, WO 2024030633, WO 2024029613, WO2024022507, WO 2024022444, WO 2024020159, WO 2024019103, WO2024017859, WO2024017392, WO 2024015731, WO 2024015262, WO 2024012456, WO 2024009191, WO2024008179, WO 2024008178, WO 2024008068, WO 2024006445, WO 2024006424, WO2024002373, WO 2023287896, WO 2023287730, WO 2023284881, WO 2023284730, WO2023284537, WO 2023283933, WO 2023283213, WO 2023280280, WO 2023280136, WO2023280026, WO 2023278600, WO 2023274383, WO 2023327324, WO 2023246914, WO2023246903, WO 2023246777, WO 2023244713, WO 2023244615, WO 2023244604, WO2023244600, WO 2023244599, WO 2023230190, WO 2023226630, WO 2023225302, WO2023225252, WO 2023220421, WO 2023219941, WO 2023217148, WO 2023215802, WO2023215801, WO 2023213269, WO 2023212548, WO 2023208005, WO 2023205719, WO2023199180, WO 2023198191, WO 2023197984, WO 2023190748, WO 2023185864, WO2023183755, WO 2023183585, WO 2023179703, WO 2023179629, WO 2023173017, WO2023173016, WO 2023173014、WO 2023172737、WO 2023171781、WO 2023159087、WO2023159086、WO 2023154766、WO 2023152255、WO 2023151674、WO 2023151621, WO2023150394, WO 2023150284, WO 2023143623, WO 2023143605, WO 2023143352, WO2023143352, WO2023143312、WO 2023141570、WO 2023141300、WO 2023138662、WO2023138601、WO 2023138589、WO 2023138524、WO 2023133183、WO 2023133181、WO2023130012、WO 2023125989、WO 2023125627、WO 2023122662、WO 2023122154、WO2023120742、WO 2023119677、WHERE 2023117681、WO 2023116934、WO 2023116895、WO2023114733、WO 2023105491、WO 2023104018、WO 2023103906、WO 2023103523、WO2023101928、WO 2023099624、WO 2023099624、WO 2023099620、WO 2023099612、WO2023099608、WO 2023099592、WO 2023098832、WHERE 2023098425, WO 2023097227, WO2023081840, WO 2023081476, WO 2023078424, WO 2023077441, WO 2023072297, WO2023072188, WO 2023066371, WO 2023064857, WO 2023061463, WO 2023061294, WO2023057985, WO 2023056951, WO 2023056421, WO 2023051586, WO 2023049697, WO2023046135, WO 2023045960, WO 2023041059, WO 2023041059, WO 2023040989, WO2023040513, WO 2023039240, WO 2023039020, WO 2023036282, WO 2023034290, WO2023030517, WO 2023030495, WO 2023030385, WO 2023030495, WO 2023030517, WO2023030685, WO 2023030687, WO2023034290, WO 2023036282, WO 2023039240, WO203020347, WO 2023025116, WO 2023287896, WO2023287730, WO 2023284881, WO2023284730, WO 2023284537, WO 2023283933, WO 2023283213, WO 2023280280, WO2023280136, WO 2023280026, WO 2023278600, WO 2023274383, WO 2023327324, WO2023040989, WO 2023039240, WO 2023039020, WO 2023036282, WO 2023034290, WO2023030517, WO 2023030495, WO 2023030385, WO 2023025116, WO 2023020523, WO2023020521, WO 2023020519, WO 2023020518, WO 2023020347, WO 2023018812, WO2023018810, WO 2023018809, WO 2023018699, WO 2023014979, WO 2023014006, WO2023004102, WO 2023003417, WO 2023001141, WO 2023001123, WO 2022271658, WO2022269508, WO 2022266167, WO 2022266069, WO 2022266015, WO 2022265974, WO2022261154, WO 2022261154, WO 2022251576, WO 2022251296, WO 2022237815, WO2022232332, WO 2022232331, WO 2022232320, WO 2022232318, WO 2022223037, WO2022221739, WO 2022221528, WO 2022221386, WO 2022216762 (e.g., compound 44 or compound 66a), WO 2022212894, WO 2022192794, WO 2022192790, WO 2022188729, WO 2022187411, WO2022184178, WO 2022173870, WO 2022173678, WO 2022135346, WO 2022133731, WO2022133038, WO 2022133345, WO 2022132200, WO 2022119748, WO2022109485, WO2022109487, WO 2022066805, WO 2022002102, WO 2022002018, WO 2021259331, WO2021257828, WO 2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO2021248082, WO 2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO2021239058, WO 2021231526, WO 2021228161, WO 2021219090, WO 2021219090, WO2021219072, WO 2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO2021215544, WO 2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO2021175199, WO 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO2021139678, WO 2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO2021126799, WO 2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO2021113595, WO 2021107160、WO 2021106231、WO 2021088458、WO 2021086833、WO2021085653、WO 2021081212、WO 2021058018、WO 2021057832、WO 2021055728, WO2021031952, WO 2021027911, WO 2021023247, WO 2020259513, WO 2020259432, WO2020234103, WO2020233592, WO 2020216190, WO 2020178282, WO 2020146613, WO2020118066, WO 2020113071, WO 2020106647, WO 2020102730, WO 2020101736, WO2020097537, WO 2020086739, WO 2020081282, WO 2020050890, WO 2020047192, WO2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO2019217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO2018218071, WO 2018218069, WO 2018217651, WO 2018206539, WO 2018143315, WO2018140600, WO 2018140599, WO 2018140598, WO 2018140514、WO 2018140513、WO2018140512、WO 2018119183、WO 2018112420、WO 2018068017、WO 2018064510、WO2017201161、WO 2017172979、WO 2017100546, WO 2017087528, WO 2017058807, WO2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768, WO2017058915, WO 2017015562、WO 2016168540, WO 2016164675, WO 2016049568, WO2016049524, WO 2015054572, WO 2014152588, WO 2014143659, WO 2013155223, CN118221700, CN 118221699, CN 118221698, CN 118221685, CN 118126064, CN 118078802, CN118078801, CN 118005656, CN 117986263, CN117986263、CN 117946135、CN 117924327、CN117903117、CN 117800990、CN 117800989、CN 117800976、CN 117736226、CN 117683051、CN117645627、CN 117624194、CN 117624190、CN 117586280、CN 117486901、CN 117466917、CN117462688、CN 117362315、CN 117327102、CN 117327094、CN 117327074、CN 117285590、CN117263959、CN117247382、CN117186095、CN117164605、CN116969977、CN116925075、CN116891489、CN116731045、CN116731044、CN116554208、CN116514846、CN116478184、CN116478141、CN116410145、CN116375742、CN116354988、CN116332948、CN116332938、CN116327956、CN 116262759、CN 116217592、CN 116199703、CN 116162099、CN 116143806、CN116143805、CN 116120315、CN 116102559、CN 115960105、CN 115894520、CN 115872979、CN115850267、CN 115785199、CN 115785124、CN 115724842、CN 115724842、CN 115721720、CN115716840、CN 115703775、CN 115611923、CN 115611898, CN 115583937, CN 115572278, CN115557949, CN 115521312, CN 115504976, CN 115490709, CN 115466272, CN 115433183, CN115433179, CN 115403575, CN 115385938, CN 115385937, CN 115385912, CN 115381786, CN115368383, CN 115368382, CN 115368381, CN115353506, CN 115322158, CN 115304623, CN115304602, CN 115197245, CN 115181106, CN 114989195, CN 114989166, CN 114989147, CN114920741, CN 114920739, CN 114907387, CN 114874234, CN 114874201, CN 114716436, CN114716435, CN 114685532, CN 114685460, CN 114591319、CN 114539293、CN 114539286, CN114539246, CN 114437107, CN 114437084, CN 114409653, CN 114380827, CN 114195804, CN114195788, CN 114437107, CN 114409653, CN 114380827, CN 114195804, CN 114057776, CN114057744, CN 114057743, CN 113999226, CN 113980032, CN 113980014, CN 113960193, CN113929676, CN 113754653、CN 113683616、CN 113563323、CN 113527299、CN 113527294、CN113527293、CN 113493440、CN 113429405、CN 113321654、CN 113248521, CN 113087700, CN113024544, CN 113004269, CN 112920183, CN 112778284, CN 112390818, CN 112390788, CN112300196, CN 112300194, CN 112300173、CN CN 112225734, CN 112142735, CN 112110918, CN112094269, CN 112047937, CN 109574871 or EP 4389751, each of which is incorporated herein by reference in its entirety, including the structures of RAS compounds disclosed therein, which are expressly incorporated herein by reference.

[0144] In the current implementation plan, we suggest that RAS(OFF) suppression is recommended for KRAS suppression, for example, select one of the following: WO 2024119277, WO 2024 120433, WO2024115890, WO 2024112654, WO 2024104453, WO 2024104425, WO 2024107686, WO2024104453, WO 2024103010, WO 2024085661, WO 2024083246, WO 2024083168, WO2024067575, WO 2024064335, WO 2024063578, WO 2024063576, WO 2024051852, WO2024051763, WO 2024046370, WO 2024044667, WO 2024041621, WO 2024041606, WO2024041589, WO 2024040131, WO 2024040109, WO 2024032747, WO 2024032704, WO2024032703, WO 2024032702, WO 2024031088, WO 2024030647, WO 2024030633, WO2024015262, WO 2024009191, WO 2024008068, WO 2024002373, WO 2023287896, WO2023274324, WO 2023246914, WO 2023246777, WO 2023230190, WO 2023215802, WO2023215801, WO 2023197984, WO 2023190748, WO 2023183585, WO 2023179703, WO2023173017, WO 2023173016, WO 2023173014, WO 2023172737, WO 2023154766, WO2023143352, WO 2023143312, WO 2023138589, WO 2023133183, WO 2023122662, WO2023114733, WO 2023099624, WO 2023099623, WO 2023099612, WO 2023099608, WO2023099592, WO 2023097227, WO 2023064857, WO 2023056421, WO2023049697、WO2023046135、WO 2023039240、WO 2023034290、WO 2023020523、WO 2023020521、WO2023020519、WO 2023020518、WO 2023001123、WO 2022271823, WO 2022261210, WO2022258974, WO 2022256459, WO 2022250170, WO 2022248885, WO 2022228543, WO2022216762, WO 2022072783, WO 2016161361, KR The following patents are incorporated herein by reference in their entirety, including the compound structures disclosed therein: 20240041720, KR 20240041719, CN118221700, CN 118126064, CN 117924327, CN 117946135, CN 117800990, CN 117800989, CN117683051, CN 117486901, CN 117263959, CN 116969977, or CN 116332948. In some embodiments, the combination therapy comprising compound A may include one or more additional RAS inhibitors, such as pan-KRAS inhibitors. In some embodiments, the combination therapy comprising a pan-KRAS inhibitor comprises ERAS-4001. In some embodiments, the pan-KRAS inhibitor is the pan-KRAS inhibitor as described in a patent application filed under the name of Medshine Discovery. In some embodiments, combinations of therapies comprising a pan-KRAS inhibitor 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.

[0145] In any embodiment described herein that employs a combination with a RAS(OFF) inhibitor, a RAS(OFF) degrading agent targeting the RAS-off state may be used. These degrading agents are known in the art. RAS degrading agents can be found in, for example, one or more of the following applications: WO 2024131777, WO 2024120424, WO 2024119278, WO 2024118966, WO 2024118960, WO 2024083258, WO 2024083256, WO 2024055112, WO 2024054625, WO 2024050742, WO2024044334, WO 2024040080, WO 2024034657, WO 2024034593, WO 2024034591, WO2024034123, WO 2024029613, WO 2024020159, WO WO 2024019103, WO 2024017392, WO2023185864, WO 2023171781, WO 2023141570, WO 2023138524, WO 2023130012, WO2023116934, WO 2023099620, WO 2023081476, WO 2023077441, CN 118126040 and CN115785199 are all incorporated herein by reference in their entirety.

[0146] In some implementations, RAS(OFF) inhibitors are peptide-based inhibitors. Peptide-based RAS(OFF) inhibitors have been developed that target specific regions of the RAS protein, such as the transition II region or the RAS-effector interface. Non-limiting examples include the K-Ras-binding peptide (Krpep-2d), the Ras-inhibiting peptide (RasIn), and LUNA18 (NCT05012618). Peptide-based RAS(OFF) inhibitors are a class of compounds that target RAS proteins by disrupting the interaction between the RAS protein and its downstream effectors or other signaling proteins. These inhibitors are typically designed to mimic the binding motif of RAS-interacting proteins or other RAS effectors (e.g., RAF or PI3K). By binding to RAS at the same site as these effectors, peptide-based inhibitors can effectively compete with these proteins and prevent activation of downstream signaling pathways. See, for example, WO 2024101402, WO 2024101386, WO 2023214576, WO 2023140329, WO 2022234853, WO 2022234852, WO2022234851 and WO 2022234639, each of which is incorporated herein by reference in its entirety.

[0147] Peptide-based RAS(OFF) inhibitors can be further divided into two main categories: inhibitors targeting the RAS-effector interface and inhibitors targeting other regions of the RAS protein. Peptide-based inhibitors targeting the RAS-effector interface are designed to bind to the transition region of RAS, which is crucial for the interaction of RAS with downstream effectors (such as RAF or PI3K). These inhibitors typically contain amino acid residues similar to those found in the binding motifs of RAS-interacting proteins or effectors, and are usually designed to form hydrogen bonds or other interactions with key residues on the RAS surface.

[0148] Peptide-based RAS(OFF) inhibitors targeting other regions of the RAS protein are typically designed to disrupt other interactions essential 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 anchoring. By binding to this region, peptide-based inhibitors prevent the proper localization of RAS to the plasma membrane, which is necessary for RAS activation and signaling.

[0149] Several common motifs have been identified as important for the binding of RAS-interacting proteins and effectors, and are frequently used in the design of peptide-based inhibitors. One example is the RAF-binding domain (RBD), present in many RAS-interacting proteins and crucial for the interaction of RAS with downstream effectors such as RAF. The RBD contains a conserved amino acid sequence (Arg-Xaa-Arg) essential for RAS binding, and this motif has been incorporated into several peptide-based inhibitors designed to disrupt the RAS-RAF interaction. Another example is the RAS-binding domain (RBD) of PI3K, important for the interaction of RAS with this downstream effector. The PI3K RBD contains several conserved amino acid residues crucial for RAS binding (e.g., Arg-Arg-Trp), and these motifs have been used to design peptide-based inhibitors targeting the RAS-PI3K interaction. Other common motifs used in peptide-based RAS(OFF) inhibitors include the Ras-binding domain (RBD) of other RAS-interacting proteins (such as RalGDS and SOS), as well as sequences that mimic the structure of the RAS transition region itself. These motifs are typically used to optimize the binding affinity and selectivity of the inhibitor to the desired target protein or interaction.

[0150] In some implementations, RAS(OFF) inhibitors are antibodies or antigen-binding peptides specific to RAS(OFF). Antibodies have been developed that bind to specific regions of RAS proteins, such as the transition II region or the RAS-effector interface. For example, antibodies targeting the transition region of RAS proteins have been developed, regions crucial for the activation of these proteins and their interaction with downstream effectors. Binding of these antibodies to the transition region prevents the conformational changes required for RAS activation and downstream signaling. Another approach involves using antibodies targeting RAS-interacting proteins or downstream effectors (e.g., RAF or PI3K). Binding of these antibodies to their target proteins disrupts RAS-dependent signaling pathways and inhibits cancer cell growth and survival. Additionally, antibodies that induce RAS protein internalization and degradation, leading to their depletion and inhibition of downstream signaling have been developed. For example, antibodies that recognize the unique structure of mutant RAS proteins and target these proteins via the ubiquitin-proteasome pathway for degradation have been developed. Non-limiting examples of KRAS(OFF)-specific inhibitory antibodies include anti-p21ser and K27 (DARPin) (see, for example, Khan et al., Biochim Biophys ActaMol Cell Res. 2020 Feb;1867(2):118570). See also WO 2024136608 and WO 2024111590, each of which is incorporated herein by reference in its entirety.

[0151] ii) SOS1 inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more SOS1 inhibitors. The SOS1 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the SOS1 inhibitor is one or more of the following: 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 of the following patent applications: WO 2023109929, WO 2023059597, WO 2023029833, WO 2023041049, WO 2023022497, WO2022157629, WO 2022184116, WO 2022170952, WO 2022170917, WO 2022171184, WO2022170802, WO 2022161461, WO 2022121813, WO 2022028506, WO 2022139304, WO2021228028, WO 2019122129, CN CN 115215847, CN 115028644, CN 114685488, CN 111393519, CN115677702 and CN115806560 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0152] iii) SHP inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more SHP inhibitors. The SHP inhibitor 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 the following: 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 of the following patent applications: WO2023282702, WO 2023280283, WO 2023280237, WO 2023018155, WO 2023011513, WO2022271966, WO 2022271964, WO 2022271911, WO 2022259157, WO 2022242767, WO2022241975, WO 2022237676, WO 2022237367, WO 2022237178, WO 2022235822, WO20222084008, WO 2022135568, WO 2022063190, WO 2022043865, WO 2022042331, WO2022033430, WO 2022017444, WO 2022007869, WO 2021259077, WO 2021249449, WO2021249057, WO 2021244659, WO 2021218755, WO 2021176072, WO 2021171261, WO2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO2021143680, WO 2021281752, WO 2021121397, WO 2021119525, WO 2021115286, WO2021110796, WO 2021088945, WO 2021073439, WO 2021061706, WO 2021061515、WO2021043077、WO 2021033153、WO2021028362, WO 2021033153, WO 2021028362, WO2021018287, WO 2020259679, WO 2020249079, WO 2020210384, WO 2020201991, WO2020181283, WO 2020177653, WO 2020165734, WO 2020165733, WO 2020165732, WO2020156243, WO 2020156242, WO 2020108590, WO 2020104635、WO 2020094104、WO2020094018、WO 2020081848、WO 2020073949、WO 2020073945、WO 2020072656、WO2020065453、WO 2020065452、WO 2020063760、WO 2020061103、WO 2020061101、WO2020033828、WO 2020033286、WO 2020022323、WO 2019233810、WO 2019213318、WO2019183367、WO 2019183364、WO 2019182960、WO 2019167000、WO 2019165073、WO2019158019、WO 2019152454、WO 2019051469、WO 2019051084、WO 2018218133、WO2018172984、WO 2018160731、WO 2018136265、WO 2018136264、WHERE 2018130928, WO2018129402, WO 2018081091, WO 2018057884, WO 2018013597, WO 2017216706, WO2017211303, WO 2017210134, WO 2017156397, WO 2017100279, WO 2017079723, WO2017078499, WO 2016203406, WO 2016203405, WO 2016203404, WO 2016196591、WO2016191328、WO 2015107495、WO 2015107494、WO 2015107493、WO 2014176488、WO2014113584、CN 115677661、CN 115677660、CN 115611869、CN115521305、CN 115490697、CN 115466273、CN 115394612、CN 115304613、CN 115304612、CN 115300513、CN115197225、CN 114957162、CN 114920759, CN 114716448, CN 114671879, CN 114539223, CN114524772, CN 114213417, CN 114195799, CN 114163457, CN 113896710, CN 113248521, CN113248449, CN 113135924, CN 113024508, CN 112920131, CN 112823796, CN 112409334, CN112402385, CN 112174935, 111848599, CN 111704611, CN 111393459, CN 111265529, CN110143949, CN 108113848, US 11179397, US 11044675, US 11034705, US 11033547, US11001561, US 10988466, US 10954243, US 10934302 or US 10858359, each of which is incorporated herein by reference in its entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0153] iv) MEK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more MEK inhibitors. The MEK inhibitor 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 pimasiteti, IMM-1-104, selmetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and bimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation selected from the following class I MEK1 mutations: D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is selected from the following class II MEK1 mutations: 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 of the following patent applications: WO2022221866, WO 2022125941, WO 2022208391, WO 2022015736, WO 2022177557, WO2021018866, WO 2021069486, WO 2021142144, WO 2021168283, WO 2021234097, WO2019076947, WO 2018233696, WO 2016188472, WO 2014063024, WO 2013019906, WO2011047238, WO 2007044515, US CN 2023032403 and CN 115813930 are incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0154] v) RAF inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more RAF inhibitors. The RAF inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the RAF inhibitor is VS-6766 or BTDX-4933. In some embodiments, the RAF inhibitor is a BRAF inhibitor. BRAF inhibitors that may be used in combination with compound A include, for example, VS6766, IK-595, vemurafenib, dabrafenib, and encorafenib. The BRAF may contain a type 3 BRAF mutation. In some implementations, the type 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 of the following patent applications: WO 2023076991, WO 2022226626, WO2022226261, WO 2019084459, WO 2018203219, WO 201851306, WO 2017212442, WO2015075483, WO 2013134243, WO 2013134298, WO 2011047238, WO 2011025965, WO2011025947, WO 2011025951, WO 2011025940, WO 2011025938, WO WO2010065893, WO2009016460, WO2009130015, WO2009111278, WO2009111279, WO2008028141 and WO2006024834 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0155] vi) ERK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more ERK inhibitors. The ERK inhibitor 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 of the following patent applications: WO 2023076305, WO 2022259222, WO 2022221547, WO 2021110169, WO2021110168, WO 2021252316, WO 2020102686, WO 2020228817, WO 2020107987, WO2019233456, WO 2019233457, WO 2016025561, WO 2016192063, WO 2016106029, WO2016106009, WO 2015051341, WO 2014124230, WO WO 2014052563, WO 2011041152, WO200910550, WO 2008153858, CN114315837, CN 115057860, CN 107973783 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0156] vii) MAPK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more mitogen-activated protein kinase (MAPK) inhibitors. The MAPK inhibitor 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 p38MAPK inhibitor or a MAP3K8 inhibitor. In some embodiments, the MAPK inhibitor is one or more of Tilpisertib (GS-4875) and neflamapidmod (VX-745). In some embodiments, reference to the term MAPK inhibitor includes any such MAPK inhibitor disclosed in any of the following patent applications: WO 2016029263, CN114767674, CN 115850179, and CN 1743006, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0157] In some embodiments, the therapeutic agent that can be combined with compound A is an inhibitor of MAP2K4. A non-limiting example of a MAP2K4 inhibitor available according to this disclosure is HRX-0233.

[0158] c) Kinase inhibitors The compositions and methods described herein may include combinations of compound A with one or more kinase inhibitors. Tyrosine kinases and serine / threonine kinases play key roles in various cellular processes, such as cell signaling, growth, and differentiation. In addition to therapies for disorders such as neurodegenerative diseases, autoimmune diseases, and inflammation, known kinase inhibitors in the art have been developed for therapies against various types of cancer.

[0159] i) PKA inhibitors In some embodiments, the compositions and methods described herein may include 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 agents described herein. In some embodiments, the PKA inhibitor is H89. In some embodiments, reference to the term PKA inhibitor includes any such PKA inhibitor disclosed in any of the following patent applications: CN 106620678 and CN 114632155, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0160] ii) FAK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more focal adhesion kinase (FAK) inhibitors. The FAK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the FAK inhibitor is one or more of the following: 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 of the following patent applications: WO2022152315, WO 2021098679, WO 2020135442, WO 2020191448, WO 2012022408, WO2013134353, WO 2012110774, WO 2010062578, CN 111072571, and KR 101691536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0161] iii) ROCK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more Rho-associated coiled-coil protein kinase (ROCK) inhibitors. The ROCK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents 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 of the following patent applications: WO 2023051753, WO 2022237892, WO 2022012409, WO 2021093795, WO2021214200, WO 2020177292, WO 202011751, WO 2019014304, WO 2019179525, WO2019089868, WO 2019014300, WO 2018108156, WO 2018009627, WO 2018009625, WO2018009622, WO 2017123860, WO 2017205709, WO WO 2016112236, WO 2014068035, WO2013030367, WO 2012146724, WO 2012067965, WO 2011107608, CN 108129453, CN108191821, CN 110917352, CN 108558823, CN108047193, CN107973777, CN108047197, CN108129448, CN 115869304 and GB202214708 are all incorporated herein by reference in their entirety, including the structures of compounds disclosed therein, which are expressly incorporated herein by reference.

[0162] iv) MSK1 inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more mitogen 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 the following: SB-747651A, SB 747651A, Ro 320432, CGP 57380, GSK2830371, SR1664, LY-3214996, PFI-4, MSC-2363318A, and AS601245.

[0163] v) RSK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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 agents described herein. In some embodiments, the RSK inhibitor is one or more of the following: BI-D1870, LJH685, SL0101-1, FMK, BRD7389, BIX 02565, 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 of the following patent applications: WO 2021249558, WO 2020165646, WO 2017141116 and CN 113801139, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0164] vi) ALK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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 the following: crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa), brigatinib (Alunbrig), lorlatinib (Lorbrena), ensartinib (X-396), TAE684, ASP3026, TPX-0131, LDK378 (a ceritinib analog), CEP-37440; 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Additional examples of 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 of the following patent applications: WO 2019142095, WO2019179482, WO 2018130928, WO 2018127184, WO 2017101803, WO 2016192132, WO2014100431, WO 2012082972, CN 111138492, CN 110526914, CN 109836415, CN 105801603, CN107987056 and CN 105878248, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0165] d) Receptor tyrosine kinase inhibitors The compositions and methods described herein may include combinations of compound A with one or more receptor tyrosine kinase inhibitors. Receptor tyrosine kinase (RTK) inhibitors are a class of molecules (e.g., small molecules, antibodies, and nucleic acids) that bind to receptor tyrosine kinases or their ligands and block the activity of the receptor tyrosine kinases or their ligands. RTKs are proteins found on the cell surface that play a crucial role in cell signaling and growth and have been developed as therapeutics for a range of diseases, including cancer, diabetes, and autoimmune disorders. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0166] i) EGFR inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more EGFR inhibitors. 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®), zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by natural ligands. Non-limiting examples of antibody-based EGFR inhibitors include those described in the following: 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 may be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, ibid.) or Mab C225 (ATCC accession number HB-8508) or antibodies or antibody fragments that have binding specificity to them.

[0167] Small molecule antagonists of EGFR include gefitinib (Iressa®), lazertinib, 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 Modifications In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some implementations, the EGFR inhibitor is osimertinib (Tagrisso®). In some embodiments, the EGFR inhibitor is one or more of cetuximab, gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif). Additional non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor 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, asciminib, futibatinib, ibrutinib, imatinib, pacritinib, or sorafenib. In some embodiments, references to the term EGFR inhibitor include any such EGFR inhibitor disclosed in any of the following patent applications: WO2023041071, WO2023049312, WO 2023020600, WO 2023284747, WO 2022206797, WO 2022258977, WO2022033416, WO 2022033410, WO 2022105908, WO 2022100641, WO 2022014639, WO2022007841, WO 2021018009, WO 2021057882, WO 2021252661, WO 2021018003, WO2021073498, WO 2021238827, WO 2020254547, WO 2020216371, WO 2020147838, WO2020207483, WO 2020254572, WO 2020001350, WO 2021001351, WO 2019164948, WO2019218958, WO 2019046775, WO 2019015655, WO 2018121758, WO 2018218963, WO2017220007, WO 2017205459, WO 2017161937, WO 2016192609, WO 199633980, WO199630347, WO 199730034, WO 199730044, WO 199738994, WO 199749688, WO 199802434, WO199738983, WO 199519774, WO 199519970, WO 199713771, WO 199802437, WO 199802438, WO199732881, WO 199833798, WO 199732880, WO 199732880, WO 199702266, WO 199727199, WO199807726, WO 1997 / 34895, WO 199631510, WO 199814449, WO 199814450, WO 199814451, WO 199509847, WO 199719065, WO 199817662, WO 199935146, WO 199935132, WO199907701, WO 199220642, DE 19629652, EP 682027, EP 837063, EP 0787772, EP 0520722, EP 0566226, CN 115960018, CN 110283162, CNCN114044774, CN111973601, CN111973602 and CN113896744 are all incorporated herein by reference in their entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0168] ii) HER2 inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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 the following: tucatinib, rastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), ado-trastuzumab emtansine (Kadcyla), and neratinib (Nerlynx). Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); and small molecule tyrosine kinase inhibitors such as gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327. In some embodiments, references to the term HER2 inhibitor include any such HER2 inhibitor disclosed in any of the following patent applications: WO 2021156178, WO 2021156180, WO 2021213800, WO 2021088987, WO2013561183 and WO 2013056108, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0169] iii) MET inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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 the following: crizotinib (Xalkori), cabozantinib (Cometriq, Cabometyx), capmatinib (Tabrecta), terpoxtinib (Tepmetko), savolitinib (Volitinib), onartuzumab (MetMab), foretinib (GSK1363089), MGCD-265 (amuvatinib), SU11274, and SU5416. In some embodiments, references to the term "MET inhibitor" include any such MET inhibitor disclosed in any of the following patent applications: WO 2022226168, WO 2021222045, WO2020047184, WO 2020015744, WO 2020244654, WO 2020156453, WO 2019206268, WO2018077227, WO 2017012539, WO 2016015653, WO 2016012963, WO 2012015677, WO2011162835, WO 2010089507, WO 2009091374, WO 2009056692, WO The following patents are incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein: 2008051547, WO2007130468, US 2012237524, CN 103497177, CN 107311983, CN 107382968, CN 110218191 and TW201331206.

[0170] iv) AXL inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more AXL inhibitors. The AXL inhibitor 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 receptor family, which also includes TYRO3 and MERTK. In some embodiments, the AXL inhibitor is one or more of the following: bemcentib, 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 of the following patent applications: WO 2023045816, WO2022237843, WO 2022246179, WO 2021012717, WO 2021088787, WO 2021067772, WO2021239133, WO 2021204713, WO 2020238802, WO 2019039525, WO 2019101178, WO2019074116, WO 2017146236, WO 2016097918, WO 2015012298, WO 2010005876, WO2010083465, CN JP 115073367 and JP 2022171109, each of which is incorporated herein by reference in its entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0171] v) IGFR inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more insulin-like growth factor receptor 1 (IGF-1R) inhibitors. IGFR inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. IGFR inhibitors have been developed that target the IGFR receptor, which plays a key role in cancer progression and metastasis. In some embodiments, the IGFR inhibitor is one or more of the following: linsitinib, AXL1717, OSI-906 (linsitinib), BMS-754807, BI 836845, 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 of the following patent applications: WO 2022115946, WO2022217923, WO 2021203861, WO 2021246413, WO 2020116398, WO 2019046600, WO2018195250, WO 2018221521, WO 2018204872, WO 2017072196, WO 2016173682, WO2015162291, WO 2015162292, WO 2010066868, WO 2006069202 and CN. 112125916, each of which is incorporated herein by reference in its entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0172] vi) RET inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more transfection rearrangement (RET) inhibitors. The RET inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. RETs play a crucial role in various cellular processes, including cell growth, differentiation, survival, and migration. RETs are activated by binding to their ligands, such as glial cell line-derived neurotrophic factor (GDNF) family ligands, which leads to the activation of downstream signaling pathways that promote these cellular processes. In some embodiments, the RET inhibitor is one or more of the following: pralsetinib, selpercatinib (LOXO-292), BLU-667, RXDX-105, TPX-0046, GSK3179106, molidustat (BAY 85-3934), and RPI-1 (Retrophin). In some embodiments, references to the term RET inhibitor include any such RET inhibitor disclosed in any of the following patent applications: WO 2021211380, WO 2021057963, WO 2021043209, WO2021222017, WO 2020035065, WO 2020114487, WO 2020200314, WO 2020200316, WO2020114494, WO 2018071447, WO 2018213329, WO 2017079140, WO 2014050781, CN113943285, CN 113683610, CN 113683611, CN 113620944, CN CN 113620945, CN 113527291, CN113527292, CN 113527290, CN 113135896, CN 111057075, CN111233899 and CN111362923 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0173] vii) ROS1 inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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 agents described herein. ROS1 is a receptor tyrosine kinase belonging to the insulin receptor family and plays a role in various cellular processes, including cell growth, differentiation, survival, and migration. In some embodiments, the ROS1 inhibitor is one or more of the following: taletrectinib, DS-6051b, TPX-0131, GZD824, and PF-06463922. In some embodiments, reference to the term ROS1 inhibitor includes any such ROS1 inhibitor disclosed in any of the following patent applications: WO 2021098703, WO 2020024825, and US 2017079972, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0174] viii) PDGFR inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more platelet-derived growth factor receptor (PDGFR) inhibitors. The PDGFR inhibitor 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 (e.g., platelet-derived growth factor (PDGF)), thereby causing activation of downstream signaling pathways that promote cell growth, proliferation, and survival. In some embodiments, the PDGFR inhibitor is one or more of the following: CP-673451, imatinib, nintedanib (ofev), sunitinib (sutent), pazopanib (votrient), regorafenib (stivarga), and dasatinib (sprycel).

[0175] ix) FGF inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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 agents described herein. FGFRs are a family of receptor tyrosine kinases consisting of four members, FGFR1–FGFR4. FGFRs are activated by binding to their ligands (fibroblast growth factor (FGF)), thereby causing activation of downstream signaling pathways that promote cell growth, 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 the following: fabatinib (TAK-659), erdafitinib (balversa), infigratinib (Truseltiq), Debio 1347, and rogaratinib (BAY 1163877). In some embodiments, references to the term "FGFR inhibitor" include any such FGFR inhibitor disclosed in any of the following patent applications: WO 2022033472, WO 2022152274, WO 2022166469, WO 2022206939, WO2021037219, WO 2021089005, WO 2021113462, WO 2020185532, WO 2019213544, WO2020164603, WO 2019154364, WO 2019034076, WO 2019213506, WO 2019223766, WO2018028438, WO 2018153373, WO 2018121650, WO WO 2018010514, WO 2017028816, WO2017118438, WO 2016134320, WO 2015008844, WO 2014172644, WO 2014007951, WO2013179033, WO 2013087578, WO 2012047699, CN 105906630, CN 115869315, CN115141176, CN 115043832 and CN 115028634, each of which is incorporated herein by reference in its entirety. 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 isolate FGF ligands and inhibit FGF signaling; and MFGR1877S, a monoclonal antibody targeting FGF ligands, designed to block FGF-mediated signaling, including the structures of the compounds disclosed therein, which are explicitly incorporated herein by reference.

[0176] x) VEGF inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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 VEGF and its receptor-mediated signaling pathways. VEGF plays a crucial role in angiogenesis (the process of forming new blood vessels from existing ones), and it is overexpressed in many cancer types, making it an attractive target for cancer therapy. 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 region that specifically binds to VEGF (e.g., bevacizumab), or a soluble VEGF receptor or its ligand-binding region, such as VEGF-TRAP™, and an anti-VEGF receptor agent (e.g., an antibody or antigen-binding region that specifically binds to it). In some implementations, the VEGF inhibitor is one or more of the following: bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, and pazopanib.

[0177] e) PI3K / mTOR pathway inhibitors The compositions and methods described herein may include combinations of compound A with one or more inhibitors of the PI3K-AKT-TOR signaling pathway. The PI3K-AKT-mTOR signaling pathway is a key intracellular pathway regulating a wide range of cellular processes, including cell growth, proliferation, metabolism, and survival. This pathway is initiated when growth factors such as insulin or IGF-1 bind to cell surface receptors and activate phosphatidylinositol 3-kinase (PI3K). Activated PI3K then phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to produce phosphatidylinositol 3,4,5-triphosphate (PIP3), which in turn activates AKT. Activated AKT then phosphorylates a variety of downstream targets, including the tuberous sclerosis complex (TSC1 / TSC2), leading to activation of 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).

[0178] i) PI3K inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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, but are not limited to, womanpemicin; 17-hydroxywomanpemicin analogs as described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methanesulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ) 235, and described in WO06 / 122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-(N-morpholinyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyprop-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinylpyridino-[3',2':4,5]furano[3,2-d]pyrimidin-2-yl]phenol hydrochloride (from Axon Medchem); PIK 75 (2-Methyl-5-nitro-2-[(6-bromoimidazolo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazine-benzenesulfonic acid monohydrochloride) (from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)nicotinamide (from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione (from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one (from Axon Medchem) Medchem); XL-765; and XL-147.Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136. In some formulations, the PI3K inhibitor is alpelisib or copanlisib.

[0179] ii) AKT inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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, but are not limited to, ipatasertib, GSK-2141795, Akt-1-1 (inhibiting Aktl) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); Akt-1-1,2 (inhibiting 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]pyridyl compounds (e.g., WO05 / 011700); indole-3-methanol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Supplement):3493S-3498S); perifol (e.g., interfering with Akt membrane localization; 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 triciribine (TCN or API-2 or NCI identifier: NSC 154020; 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 described in Cancer (Basel) Sep 2015; 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.

[0180] iii) mTOR inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more mTOR inhibitors. The mTOR inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94 / 09010); and ridaforolimus. (Also known as deforolimus or AP23573); rapamycin analogs, such as those disclosed in WO98 / 02441 and WO01 / 14387, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropionate]-rapamycin (also known as CC1779); 40-epi-(tetrazole)-rapamycin (also known as ABT578); 32-deoxyrapamycin; 16-pentynyloxy-32(S)-dihydrorapamycin; derivatives disclosed in WO05 / 005434; U.S. Patent No. 5,258,389 Derivatives disclosed in Nos. 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842 and 5,256,790, and WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g. WO05 / 016252). In some implementations, the mTOR inhibitor is a dual-site inhibitor (see, for example, WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552.

[0181] iv) MNK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more mitogen-activated protein kinase-interacting kinase (MNK) inhibitors. The MNK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. MNK proteins are activated downstream of the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a crucial role in the regulation of cell proliferation, differentiation, and survival. MNK phosphorylates eIF4E, a key component of the eukaryotic translation initiation complex, which enhances the translation of specific mRNAs, including those encoding proteins involved in cell cycle regulation and tumorigenesis. In some embodiments, the MNK inhibitor is one or more of tomivoserte (eFT508), CGP57380, and SEL201. In some embodiments, references to the term MNK inhibitor include any such MNK inhibitor disclosed in any of the following patent applications: WO 2021098691, WO 2020108619, WO 2020086713, WO 2018152117, WO 2018228275, WO2015200481 and CN115583942, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0182] v) eIF4 inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more eukaryotic initiation factor 4A (eIF4A) inhibitors. The eIF4A inhibitor 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, where it acts as an RNA helicase to unravel the secondary structure of mRNA and facilitate ribosome binding. eIF4A is essential for the translation of many cancer-related genes, making it an attractive therapeutic target for cancer treatment. In some embodiments, the eIF4A inhibitor is one or more of zotatifin (eFT226), silvestrol, pateamine A, and rocaglate. In some embodiments, references to the term eIF4A inhibitor include any such eIF4A inhibitor disclosed in any of the following patent applications: WO 2023034813, WO 2021195128 and WO2017091585, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0183] In some embodiments, the compositions and methods described herein may include one or more eukaryotic initiation factor 4G (eIF4G) inhibitors. The eIF4G inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The eIF4G family includes several proteins involved in protein translation initiation. eIF4G acts as a scaffold for other proteins, including eIF4E and eIF4A, to form the eIF4F complex, which is responsible for binding to the 5' cap of mRNA and unwinding the secondary structure of the mRNA to allow ribosome scanning and translation initiation. In some embodiments, the eIF4G inhibitor is one or more of patamide A and equistallol.

[0184] f) DNA damage response inhibitors The compositions and methods described herein may include combinations of compound A with one or more DNA damage response (DDR) inhibitors. The DDR pathway is a key cellular pathway activated in response to DNA damage and is essential for maintaining genomic stability, thereby preventing cancer development. However, cancer cells often have defects in the DDR pathway, making them more sensitive to DDR inhibitors. DDR inhibitors have shown promise as potential cancer therapeutics in preclinical studies, especially in combination with other agents.

[0185] i) Wee1 inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A and one or more Wee1 inhibitors. Wee1 is a kinase that plays a key role in regulating the cell cycle by inhibiting the activity of cyclin-dependent kinases (CDKs) and preventing cell progression through the G2 / M checkpoint. Wee1 is overexpressed in several cancer types and is associated with tumor growth and survival. In some embodiments, the Wee1 inhibitor is one or more of imp7068, adarosetib, or ZNL-02-096. In some embodiments, references to the term Wee1 inhibitor include any such Wee1 inhibitor disclosed in any of the following patent applications: WO 2022011391, WO2022247641, WO 2021043152, WO 2020221358, WO 2020083404, WO 2020192581, WO2019085933, WO 2018133829, WO 2015115355, WO 2015183776, WO 2014085216 and CN114831993, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0186] ii) CHK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more checkpoint kinase (CHK) inhibitors. The CHK inhibitor 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 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 of rabusertib, LY2606368, GDC-0575, and MK-8776. In some embodiments, references to the term CHK1 inhibitor include any such CHK1 inhibitor disclosed in any of the following patent applications: WO 2021113661, WO 2021104461, WO 2019012030, WO2010118390, WO 2008067027, WO 2002070494 and TW202126818, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0187] iii) ATM inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more telangiectatic ataxia mutation (ATM) inhibitors. The ATM inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. ATM plays a role in regulating replication stress responses and maintaining genomic stability. In some embodiments, the ATM inhibitor is one or more of M4076, AZD0156, KU-60019, and VE-821. In some embodiments, reference to the term ATM inhibitor includes any such ATM inhibitor disclosed in any of the following patent applications: WO 2021197339, WO 2021098734, WO 2021260580, WO 2007026157, WO2006085067, and US 2016113935, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0188] iv) ATR inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more telangiectatic ataxia and Rad3-related (ATR) inhibitors. The ATR inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the ATR inhibitor is one or more of the following: ceralaertib, 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 of the following patent applications: WO 2023016529, WO 2022237875, WO 2022268025, WO2021012049, WO 2021023272, WO 2021260579, WO 2021228758, WO 2019050889, WO2019154365, WO 2019133711, WO 2017059357, WO 2013049859, WO 2007046426, WO2007015632 and CN113797341, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0189] v) PARP inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more poly(ADP-ribose) polymerase (PARP) inhibitors. The PARP inhibitor 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 end-anchored polymerase) 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 PARP enzyme activity, leading to the accumulation of DNA damage and ultimately cell death. In some embodiments, the PARP inhibitor is one or more of olaparib, rucaparib, niraparib, and veliparib (ABT-888). In some embodiments, references to the term PARP inhibitor include any such PARP inhibitor disclosed in any of the following patent applications: WO 2023051812, WO 2023051807, WO2023051716, WO 2023278592, WO 2022228387, WO 2022022664, WO 2022000946, WO2022222921, WO 2021163530, WO 2020122034, WO 2020239097, WO 2020142583, WO2020156577, WO 2020098774, WO 2020196712, WO 2019200382, WO 2018125961, WO2018205938, WO 2018192576, WO 2018218025, WO 2017032289, WO 2017177838, WO2017029601, WO 2017088723, WO 2016155655, WO 2015154630, WO 2013097225, WO2012130166, WO 2011006794, WO 2009046205, WO 2009063244, WO 2008084261, WO2007138351, WO 2006110816, WO 2005053662, WO CN1005012524, CN113698356, CN113603647, CN115073544, CN108938634, CN104887680, CN110343088, CN108976236 and CN107629071 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0190] vi) DNA-PK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more DNA-dependent protein kinase (DNA-PK) inhibitors. The DNA-PK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. DNA-dependent protein kinase (DNA-PK) is a serine / threonine protein kinase that plays a crucial role in DNA repair and maintenance of genome stability. In some embodiments, the DNA-PK inhibitor is one or more of 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 of the following patent applications: WO2022187965, WO 2021197159, WO 2021260583, WO 2021204111, WO 2021104277, WO2021098813, WO 2021022078, WO 2020259613, WO 2019143678, WO 2019143675, WO2019201283, WO 2015058031, WO 2014159690, WO 2012028233, WO 2009010761, WO2006032869, WO 2006109084, CN CN 112574179, CN 112300132 and CN 112300126 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0191] g) Cell cycle inhibitors The compositions and methods described herein may include combinations of compound A 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 of cyclins 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, leading to 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, leading to 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, leading to cell cycle arrest and / or apoptosis.

[0192] i) CDK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more CDK inhibitors. The CDK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Cyclin-dependent kinases (CDKs) are a family of protein kinases that regulate cell division and proliferation. Cell cycle progression is controlled by cyclins and their associated cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, and CDK6), while other CDKs such as CDK7, CDK8, and CDK9 are essential for transcription. The binding of CDKs to cyclins forms a heterodimeric complex that phosphorylates their substrates at serine and threonine residues, thereby triggering events required 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 of palbociclib, ribociclib, abemaciclib, and trilaciclib. In some embodiments, the CDK inhibitor is one or more of the following: tagtociclib (PF-07104091), seliciclib, voruciclib P1446A-05, BLU-222, dinaciclib, AT-7519, RGB286638, and AZD4573.

[0193] In some embodiments, references to the term CDK inhibitor include any such CDK inhibitor disclosed in any of the following patent applications: WO 2022166793, WO 2022187611, WO 2022130304, WO2021227906, WO 2021057867, WO 2020207260, WO 2020138370, WO 2020125513, WO2020148635, WO 2020215156, WO 2020052627, WO 2017177837, WO 2017162215, WO2017177836, WO 2016193939, WO 2016014904, WO 2016015598, WO WO2016015605, WO2015181737, WO 2012061156 A1, WO 2012038411, WO 2010020675, WO 2010125004, WO2007139732, WO 2006024945, CN 114478529, CN 108794496, CN 105294737, CN107652284, KR 20180106188 and US 2017152269 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0194] ii) Aurora kinase inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more aurora kinase inhibitors. The aurora kinase inhibitor 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 crucial role in regulating cell division and maintaining genome 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 of pebocilib, ribociclib, and abecicilib. In some embodiments, the aurora kinase inhibitor is one or more of alisertib, danusertib, barasertib, and MLN8237. In some embodiments, references to the term "aurora kinase inhibitor" include any such aurora kinase inhibitor disclosed in any of the following patent applications: WO 2021110009, WO2021008338, WO 2020112514, WO 2019129234, WO 2016077161, WO 2013143466, WO2011103089, WO 2010081881, WO 2010133794, WO 2009134658, WO 2008001886, WO2007095124, WO 2007003596, WO 2006129064, CN 114276227, CN 108078991, CN106543155, CN CN 104211692 and CN 104098551 are each incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0195] iii) PLK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more polo-like kinase (PLK) inhibitors. The PLK inhibitor 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 crucial role in regulating cell division, DNA damage responses, and mitotic progression, and consist of four members: PLK1, PLK2, PLK3, and PLK4. In some embodiments, the PLK inhibitor is one or more of volasertib, onvansertib, BI 2536, and GSK461364. In some embodiments, references to the term PLK inhibitor include any such PLK inhibitor disclosed in any of the following patent applications: WO 2011012534 A1, WO 2010065134, WO 2009130453, WO2009042806, WO 2004043936, WO 2007030361, WO 2006021547, CN 115804777 and EP2325185, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0196] iv) Inhibitors of the microtubule motor protein kinesin superfamily In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more kinesin (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 agents described herein. KSP and KIF are subsets of the microtubule motor kinesin superfamily. KSP, also known as Eg5, is a member of the motor kinesin superfamily and plays a key role in spindle formation and cell division during mitosis. 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 the following: SB743921, monastrol, S-triphenylmethyl-L-cysteine ​​(STLC), and filanesib (ARRY-520). In some embodiments, the KIF inhibitor is an inhibitor of a kinesin-8 family microtubule motor protein. 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 kinin superfamily inhibitor" include any such microtubule motor protein kinin superfamily inhibitor disclosed in any of the following patent applications: WO 2015114854, WO 2015114855, WO 2010084186, WO 2006101761, WO2006110390, WO 2006044825, WO 2006078574, WO 2005060654, WO 2004092147, WO2004037171, WO 2004058700, WO 2003050064, WO 2003105855, WO 2022037665, WO2018114804, WO 2017162663, WO 2016207089, WO 2012073375, JP 2014162787, JP2019189590, JP2013166713 and KR 20220145566 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0197] v) DYRK1 inhibitors In some embodiments, the compositions and methods described herein may comprise a combination of compound A with one or more bispecific tyrosine phosphorylation-regulated kinase 1 (DYRK1) inhibitors. The DYRK1 inhibitor 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 important role in various cellular processes, including cell cycle regulation, neuronal development, and transcriptional control. In some embodiments, the DYRK1 inhibitor is one or more of dehydrocamelin, INDY, D4476, and AZ191. In some embodiments, reference to the term DYRK1 inhibitor includes any such DYRK1 inhibitor disclosed in any of the following patent applications: WO 2023277331 A1, WO 2023140846 A1, WO 2017181087 A1, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0198] h) Anti-apoptosis protein inhibitors The compositions and methods described herein may include a combination of compound A 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 and / or any additional therapeutic agents described herein. Anti-apoptotic inhibitors target proteins that play a role in preventing 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 apoptotic pathways, thereby preventing cell death. Several known classes of anti-apoptotic inhibitors exist, including Bcl-2 inhibitors, XIAP inhibitors, survivin inhibitors, Mcl-1 inhibitors, and FLIP inhibitors. These inhibitors work 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 include one or more anti-apoptotic protein inhibitors. The anti-apoptotic protein inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor and / or any additional therapeutic agents described herein. In some embodiments, the anti-apoptotic protein inhibitor includes an MCL-1 inhibitor. Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845. Myeloid leukemia-1 (MCL-1) protein is a key anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance, not only to conventional chemotherapy but also to targeted therapies, including BCL-2 inhibitors such as ABT-263. In some embodiments, anti-apoptotic protein inhibitors include BCL protein inhibitors. Examples of BCL protein inhibitors include, but are not limited to, Venetoclax (Venclexta), Navitoclax (ABT-263), A-1331852, S63845, and AT-101.

[0199] i) Autophagy inhibitors The compositions and methods described herein may include combinations of compound A 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, bafloxacin A1, 5-amino-4-imidazolamide riboside (AICAR), leucocyanidin, autophagy-inhibiting 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. Additionally, antisense RNA or siRNA that inhibits the expression of proteins, including but not limited to ATG5 (involved in autophagy), may be used. In some embodiments, one or more additional therapies include autophagy inhibitors.

[0200] a) ULK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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 agents described herein. In some embodiments, the ULK inhibitor is a ULK1 / 2 inhibitor. In some embodiments, the ULK inhibitor is one or more of the following: ULK-101, MRT68921, SBI-0206965, MRT67307, MRT68920, MRT68922, MRT199665, LY3009120, and doxomorphin.

[0201] b) VPS inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more vacuole 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 key role in autophagy by regulating the formation and function of autophagosomes, structures that engulf cellular components and transport them to lysosomes for degradation. Dysregulation of VPS proteins is associated with a variety of diseases, including cancer, neurodegenerative diseases, and infectious diseases. In some embodiments, the VPS inhibitor is a VPS34 inhibitor. In some embodiments, the VPS inhibitor is one or more of the following: PIK-III, VPS34-IN1, SAR405, Spautin-1, and NSC185058.

[0202] c) Inhibitors of macropinocytosis In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more macropinocytosis inhibitors. The macropinocytosis inhibitor may be administered or formulated in combination with a RAS(ON) inhibitor and / or any additional therapeutic agent described herein. A macropinocytosis inhibitor is a compound that blocks or reduces the macropinocytosis process. In some embodiments, the macropinocytosis inhibitor is one or more of the following: EIPA (ethyl isopropyl amiloride), woumacillin, amiloride, apilimod, Dyngo-4a, and erythropoietin B.

[0203] j) Inhibitors of the WNT / β-catenin pathway The compositions and methods described herein may include combinations of compound A with one or more WNT / β-catenin pathway inhibitors. In some embodiments, the WNT / β-catenin pathway inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The WNT / β-catenin pathway is an important signaling pathway that plays a crucial role in development, tissue homeostasis, and disease. Dysregulation of this pathway is associated with various cancers, making it an attractive target for cancer therapy. WNT / β-catenin pathway inhibitors target various components of the pathway, including WNT ligands, receptors, and downstream effectors.

[0204] i) β-catenin inhibitors In some embodiments, the compositions and methods described herein may include compound A and one or more β-catenin inhibitors. The β-catenin inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. β-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 the disruption complex, which marks the degradation status of β-catenin. However, in many cancer cells, the disruption complex is impaired, leading to the accumulation of β-catenin in the cell nucleus and its involvement in the activation of target genes for tumor growth and metastasis.In some implementations, the WNT / β-catenin inhibitor is one or more of the following: 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, IWP L6, 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, Salinomycin, BMD4702, 3289-8625, J01-017a, FJ9, KY-02061, KY-02327, NSC668036, Peptide Pen-N3, SSTC3, CCT031374, TCS 183, XAV939, AZ1366, G007-LK, MSC2504877, G244-LM, IWR-1, JW74, JW55, K-756, NVP-TNKS656, MN-64, RK-287107, WIKI4, KY1220, KYA1797K, MSAB, PKF115-584, CGP049090, AV-65, PNU-74654, Windorphen, IQ-1 (tegavivant), foscenvivant, PNPB-29, ZW4864, SAH-BCL9, oxalic acid, xStAx-VHL, NRX-252114, cetuximab (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 of the following patent applications: CN 104388427 and CN 103830211, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0205] ii) PORCN inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more porcupine protein (PORCN) inhibitors. The PORCN inhibitor 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 that plays a key role in the WNT signaling pathway by mediating palmitoylation of WNT ligands. This palmitoylation is essential for the secretion and signaling activity of WNT proteins. Inhibition of PORCN leads to reduced WNT signaling activity. In some embodiments, the PORCN inhibitor is one or more of the following: LGK974 (WNT974), ETC-1922159, CGX1321, and CWP232291.

[0206] iii) GSK3 inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more glycogen synthase kinase (GSK3) inhibitors. The GSK3 inhibitor 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 many cellular processes, including glycogen metabolism, cell cycle regulation, and Wnt signaling. GSK inhibitors have been investigated as potential therapeutic agents for various diseases, including cancer, diabetes, Alzheimer's disease, and bipolar disorder. In some embodiments, the GSK3 inhibitor is one or more of the following: tideglusib, laduviglusib, 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 of the following patent applications: WO 2017153834, WO 2014059383, WO 2010012398, WO 2009017455, WO2003037891, CN 107151235 and CN 102258783, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0207] iv) CLK inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more Cdc2-like kinase (CLK) inhibitors. The CLK inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. CLK (Cdc2-like kinases) are a family of serine / threonine kinases that play a crucial role in the regulation of precursor mRNA splicing, specifically alternative splicing. The CLK family has four members: CLK1, CLK2, CLK3, and CLK4. The CLK kinase family 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 the following: Lorecivivint, SM08502, SM04690, TG003, KH-CB19, Cmpd-1, T3.5, and CX-4945. In some implementations, references to the term CLK inhibitor include any such CLK inhibitor disclosed in WO 2020006115, which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0208] k) JAK / STAT pathway inhibitors The compositions and methods described herein may include a combination of compound A 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 agents described herein. The Janus kinase / signal transduction and activator of transcription (JAK / STAT) pathway is a signaling pathway involved in many cellular processes, including immune responses, cell growth, and differentiation. Dysregulation of this pathway is associated with a variety of diseases, including inflammatory conditions, 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 implementations, the JAK inhibitor is one or more of the following: ruxotinib (Jakafi®), paclinib, fedatinib (Fedratinib), tofacitinib (Xeljanz®), abrocitinib, filgotinib, olatinib, peficitinib, upadacitinib, deucravacitinib, delgocitinib, and baricitinib (Olumiant®). In some embodiments, references to the term JAK inhibitor include any such JAK inhibitor disclosed in any of the following patent applications: WO 2023011301, WO 2023201044, WO2022143629, WO 2022251434, WO 2022067106, WO 2022033551, WO 2021244323, WO2021238817, WO 2021238818, WO 2021178991, WO 2021136345, WO 2021190647, WO2020219639, WO 2020182159, WO 2020155931, WO 2020038457, WO WO2020219524, WO2020173400, WO 2018204233, WO 2018204238, WO 2018169875, WO 2018117152, WO2017215630, WO 2016070697, WO 2016027195, CN 117815195, CN117815367 and CN115969796 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0209] In some embodiments, the JAK / STAT pathway 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 the following: TTI-101, C-188-9, WP1066, VVD-130850, LLL12B, STA-21, SD-36, Static, S3I-201, OPB-31121, and Napabucasin (BBI608). In some embodiments, references to the term STAT inhibitor include any such STAT inhibitor disclosed in any of the following patent applications: WO 2024030628, WO 2023164680, WO 2023192960, WO2023133336, WO2020206424, WO 2023107706, WO 2021150543, WO 2008151037 and CN109288845, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0210] l) Epigenetic regulators The compositions and methods described herein may include combinations of compound A with one or more epigenetic regulators. Epigenetic regulators are a class of therapeutic agents that target enzymes responsible for modifying the structure and function of chromatin, a complex of DNA and proteins that make up chromosomes. These enzymes, including histone deacetylases (HDACs), histone methyltransferases (HMTs), and DNA methyltransferases (DNMTs), play a crucial role in gene expression and regulation by modifying DNA packaging and influencing its reading and transcription. Epigenetic regulators act by altering the activity of these enzymes (by inhibiting or enhancing their function), thereby regulating gene expression in specific ways. 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 conditions, and neurological disorders.

[0211] i) HDAC inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more histone deacetylase (HDAC) inhibitors. HDAC inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Several classes of HDACs exist, including class I, IIa, IIb, III, and IV. Class I HDACs are further subdivided into HDAC1, HDAC2, HDAC3, and HDAC8, while class IIa HDACs include HDAC4, HDAC5, HDAC7, and HDAC9. Class IIb HDACs consist of HDAC6 and HDAC10, and class III HDACs are referred to as sirtuins. HDAC inhibitors can target different classes of HDACs, and their specific effects on gene expression may vary depending on the HDAC they target. In some implementations, the HDAC inhibitor is one or more of the following: vorinostat (Zolinza), romidepsin (Istodax), belinostat (Beleodaq), panobinostat (Farydak), entinostat (MS-275), valproic acid (Depakene), trichostatin A (TSA), sodium butyrate, and mocetinostat (MGCD0103). Non-limiting examples of HDAC inhibitors include trichostatin, sodium butyrate, aspirin, succinylaminophenamide, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat. In some embodiments, references to the term HDAC inhibitor include any such HDAC inhibitor disclosed in any of the following patent applications: WO 2022110958, WO2021252628, WO 2019204550, WO 2018178060, WO 2016126724, WO 2014143666, WO2013041480 and WO 2006120456, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0212] ii) BET inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more bromodomain and superterminal (BET) protein 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 superterminal) proteins are a family of epigenetic reader proteins that recognize and bind to acetylated lysine residues on histones, thereby leading to chromatin remodeling and regulation of gene expression. There are four BET proteins in humans: BRD2, BRD3, BRD4, and BRDT. BET inhibitors specifically target the bromodomains of BET proteins, inhibiting their binding to acetylated lysine residues on histones and leading to alterations in gene expression. BET inhibitors can be used to treat cancer and other diseases characterized by dysregulation of gene expression. In some embodiments, the BET inhibitor is one or more of the following: 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 of the following patent applications: WO2022046682, WO 2022182857, WO 2021107657, WO 2021107656, WO 2020221006, WO2020053660, WO 2018097977, WO 2017222977, WO 2017142881, WO 2015075665, WO2015011084 and CN 113264930, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0213] iii) EZH2 inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A 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 and a member of the polycomb repressor complex 2 (PRC2) family. EZH2 plays a key role in gene expression regulation, specifically by catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), causing 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 the following: tazemetostat, GSK2816126, and CPI-1205 (lirametostat). In some embodiments, references to the term "EZH2 inhibitor" include any such EZH2 inhibitor disclosed in any of the following patent applications: WO 2023030299, WO 2022179584, WO 2020224607, WO2021243060, WO 2021086069, WO 2019206155, WO 2018133795, WO 2018137639, WO2017184999, WO 2017218953, WO 2016201328, WO 2015195848, WO 2013155317, WO2013138361, and CN. 114621191, each of which is incorporated herein by reference in its entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0214] iv) Co-REST inhibitors In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more Co-REST inhibitors. The Co-REST inhibitor 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 a variety of transcription factors to regulate gene expression. Co-REST functions by recruiting histone deacetylases (HDACs) to chromatin, causing repression of gene expression. Inhibition of Co-REST has been proposed as a potential therapeutic strategy for various diseases, including neurodegenerative diseases and cancer. In some embodiments, the co-REST inhibitor is one or more of the following: nocodazole, NSC1892, and astaxanthin.

[0215] v) EP300 In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more E1A-binding protein p300 (EP300) inhibitors. The EP300 inhibitor 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 responses, and cell cycle progression. EP300 acts as a histone acetyltransferase, catalyzing the transfer of acetyl groups to lysine residues on histones, leading to changes in chromatin structure and gene expression. EP300 activity is associated with diseases such as cancer, cardiovascular diseases, 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 of the following patent applications: WO 2021213521 and WO 2016044694, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0216] vi) LSD1 In some embodiments, the compositions and methods described herein may include a combination of compound A 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 key role in regulating gene expression through histone modification. It specifically removes a methyl group from lysine 4 on histone 3, thereby leading to gene repression. Dysregulation of LSD1 is associated with a variety of diseases, including cancer and neurodegenerative diseases. In some embodiments, the LSD1 inhibitor is one or more of the following: 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 of the following patent applications: WO 2021095840, WO 2021175079, WO 2021058024, WO2020047198, WO 2020052649, WO 2020015745, WO 2020052647, WO 2018137644, WO2017184934, WO 2017027678, WO 2017116558, WO 2017149463, WO 2016161282, WO2015123465, WO 2015123424, WO 2013057322, WO 2013057320, WO CN1012135113, CN114805261, CN111072610, CN107174584, CN110478352, CN106432248 and CN106045881 are all incorporated herein by reference in their entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0217] vii) PRMT5 In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more protein arginine methyltransferase 5 (PRMT5) inhibitors. The PRMT5 inhibitor 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 and catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to a nitrogen atom of an arginine residue in a target protein. PRMT5 is involved in various biological processes, including gene expression regulation, signal transduction, and DNA repair. In some embodiments, the PRMT5 inhibitor is one or more of the following: 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 of the following patent applications: WO2023001133, WO 2022206964, WO 2022153161, WO 2021068953, WO 2021088992, WO2020259478, WO 2020205660, WO 2020250123, WO 2020033288, WO 2019102494, WO2019112719, WO 2019180631, WO 2018065365, WO 2017153186, WO 2017212385, WO2017032840, WO 2016022605, WO2014100695, WO 2014145214, WO 2014100719, CN111825656, CN 114558014, CN 11304554 and CN 112778275 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0218] viii) MAT2A In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more methionine adenosyltransferase 2A (MAT2A) inhibitors. The MAT2A inhibitor 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), which is an important cofactor in many biological processes, including DNA methylation, protein methylation, and polyamine synthesis. Elevated MAT2A expression is associated with various cancers. In some embodiments, the MAT2A inhibitor is one or more of the following: cyclic leucine and 2-hydroxy-4-methylthiobutyric acid. In some embodiments, references to the term MAT2A inhibitor include any such MAT2A inhibitor disclosed in any of the following patent applications: WO 2022256808, WO2022256806, WO 2019191470 and CN 115716831, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0219] ix) DOT1L In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more telomere silencing interferon 1-like (DOT1L) inhibitors. The DOT1L inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. DOT1L is a histone methyltransferase that catalyzes the methylation of lysine 79 on histone H3. This modification is associated with 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 the following: EPZ-5676 (pinometostat) and EPZ-004777. In some embodiments, references to the term DOT1L inhibitor include any such DOT1L inhibitor disclosed in any of the following patent applications: WO 2016090271, WO 2014100662 and CN 108997480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0220] iix) UBA1 In some embodiments, the compositions and methods described herein may include a combination of compound A 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 of protein degradation and regulation. Ubiquitination involves the covalent linkage of ubiquitin molecules to target proteins, marking their degradation by the proteasome or regulating their activity, localization, or interaction within the cell. Several inhibitors have been developed to modulate UBA1 activity, aiming to disrupt ubiquitination-mediated processes in diseased cells. These inhibitors include (but are not limited to) adenosine-based inhibitors, which typically compete with ATP for binding to the active site of UBA1, thereby preventing activation by ubiquitin (e.g., PYR-41 and MLN7243); covalent inhibitors, which form irreversible bonds with specific amino acid residues at the active site of UBA1, thereby inhibiting its activity (e.g., TAK-243 (formerly known as MLN4924)); allosteric inhibitors, which bind to sites on UBA1 different from the active site, thereby inducing conformational changes that inhibit its catalytic activity (e.g., compound 2i); and fragment-based inhibitors, which are 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 of the following patent applications: WO 2016069393A1, WO 2016069392 A1 and JP 2013237627 A2, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0221] m) Additional therapeutic agents that can be used in combination therapy In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more farnesyltransferase inhibitors. The farnesyltransferase inhibitor 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 farnesyltransferases, which function in a process called protein isoprenelation. Protein isoprenelation is an important step in the activation of certain proteins involved in signal transduction, cell growth, and differentiation. In some embodiments, the farnesyltransferase inhibitor is one or more of tipifarnib, lonafarnib, and rilapladib. In some embodiments, references to the term farnesyltransferase inhibitor include any such farnesyltransferase inhibitor disclosed in any of the following patent applications: WO 2010057028, WO 2007042465, WO200136395, WO 200064891, WO 200042849, WO 199938862, WO 199928315, WO 199829390, WO199426723, CN 107312000, CN 107365310, KR 100375421, KR 100388790, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0222] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more casein kinase inhibitors. In some embodiments, the casein inhibitor is SR-3029, a potent and ATP-competitive inhibitor of CK1δ and CK1ε.

[0223] In some embodiments, the compositions and methods described herein may include a combination of one or more FLT3 inhibitors 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 of blood cell formation. It is primarily expressed on hematopoietic stem cells (HSCs) and progenitor cells in the bone marrow, where it 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.

[0224] In some embodiments, the compositions and methods described herein may include a combination of compound A and 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 agents described herein. TGFβ (transforming growth factor β) is a multifunctional cytokine involved in various cellular processes, including cell growth, differentiation, apoptosis, and immune responses. Dysregulation of the TGFβ signaling pathway is associated with various diseases, including cancer, fibrosis, and autoimmune disorders. In some embodiments, the TGFβ inhibitor is one or more of galunisertib (LY2157299) and vactosertib (TEW-7197). In some implementations, the TGFβ inhibitor is one or more of the following: galuniseci, LY2157299, non-hematoxylin and erythromycin (Fresolimumab), ledelimumab, tramedersen, curcumin, resveratrol, and small interfering RNA (siRNA) to silence TGFβ receptor expression. In some embodiments, references to the term TGFβ inhibitor include any such TGFβ inhibitor disclosed in any of the following patent applications: WO 2023043473, WO2020104648, WO 2020128850, WO 2016140884, WO 2007018818, WO 2004024159, WO200226935, WO 2002062753, WO 2002062776 and JP 2012087076, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0225] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more HSP90 inhibitors. The HSP90 inhibitor 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 a large number of client proteins involved in various cellular processes, including cell cycle progression, signal transduction, and apoptosis. In some embodiments, the HSP90 inhibitor is one or more of the following: gerdanamycin and its derivatives (e.g., 17-AAG, 17-DMAG), KOS 953, rhizobacterin and its derivatives (e.g., PU-H71), SNX-2112, Ganetspib, AT13387, Onalespib, Luminespib, and KW-2478. In some embodiments, references to the term HSP90 inhibitor include any such HSP90 inhibitor disclosed in any of the following patent applications: WO 2021137665, WO 2018200534, WO2017151425, WO 2015200514, WO 2013053833, WO 2013009657, WO 2013119985, WO2012138894, WO 2011044394, WO 2009097578, WO 2008115719, CN 105237533 and CN104030904, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0226] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more glutathione peroxidase 4 (GPX4) inhibitors. The GPX4 inhibitor 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 acts as a regulator of ferroptosis (a regulated form of cell death driven by lipid peroxidation). In some embodiments, the GPX4 inhibitor is one or more of the following: 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 of the following patent applications: WO 2021132592, US 2021244715, and KR 20220115536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0227] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more NRF2 inhibitors. The NRF2 inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. NRF2 is a transcription factor that regulates gene expression involved in cellular antioxidant responses, detoxification, and other cell-protective pathways. It plays a key 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 the following: ML385, crotonol, CDDO-Im, RTA-408, and trigonelline. In some embodiments, reference to the term NRF2 inhibitor includes any such NRF2 inhibitor disclosed in any of the following patent applications: WO 2023051088, WO 2021202720, KR 2022013610, and CN107519168, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0228] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more TEA domain (TEAD) inhibitors. TEAD inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. TEADs are 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 coactivators that bind to DNA through their conserved TEA domains and interact with other transcription factors to activate the expression of target genes. In some implementations, the TEAD inhibitor is one or more of the following: 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 of the following patent applications: WO 2023280254, WO2023031781, WO 2022258040, WO 2020070181, WO 2018185266, and WO 2017064277, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0229] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more NOTCH / γ secretase inhibitors. The NOTCH / γ secretase inhibitor may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. In some embodiments, the NOTCH / γ secretase inhibitor is nirogacestat. In some embodiments, references to the term NOTCH / γ secretase inhibitor include any such NOTCH / γ secretase inhibitor disclosed in any of the following patent applications: WO 2020208572, WO2017200969, WO 2014047390, WO 2014047372, WO 2011041336, WO 2010090954, WO2009008980, WO 2009087130, WO 2007110335, CN 103664904, CN 105560244 and KR20200077480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0230] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more hedgehog protein inhibitors. The hedgehog protein inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. The hedgehog (Hh) protein family are secreted signaling molecules that play a crucial role in adult embryonic development and tissue homeostasis. The Hh signaling pathway is involved in regulating cell growth, differentiation, and survival. In some embodiments, the hedgehog protein inhibitor is one or more of Vismodegib (Erivedge), Sonidegib (Odomzo), and Glasdegib (Daurismo). In some embodiments, reference to the term hedgehog protein inhibitor includes any such hedgehog protein inhibitor disclosed in any of the following patent applications: WO 2011063309 and CN 107163028, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0231] The compositions and methods described herein may include combinations of compound A with one or more NF-κB pathway inhibitors. NF-κB inhibitors may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. NF-κB (NFκB) is a family of transcription factors involved in the regulation of various cellular processes, including inflammation, immunity, cell survival, and proliferation. Non-limiting examples of NF-κB inhibitors include bortezomib (Velcade), curcumin, parthenolide, IKK inhibitors (e.g., IKK-16, BAY 11-7082), resveratrol, andrographolide, and proteasome inhibitors (e.g., MG132, lactocinol).

[0232] In some embodiments, the additional therapy is the administration of a side effect mitigator (e.g., an agent intended to reduce the occurrence or severity of treatment side effects). For example, in some embodiments, compound A may also be used in combination with a therapeutic agent for treating nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0233] In some embodiments, one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy). In some embodiments, one or more additional therapies include therapeutic agents (e.g., compounds or biologics 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-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biologics that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors).

[0234] Examples of non-pharmacological treatments include, but are not limited to, radiotherapy, cryotherapy, thermotherapy, surgery (e.g., surgical removal of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0235] In some implementations, compound A can be used as postoperative adjuvant therapy. In some implementations, compound A can be used as preoperative neoadjuvant therapy.

[0236] Radiation therapy can be used to inhibit abnormal cell growth or treat hyperproliferative conditions, such as cancer, in subjects (e.g., mammals, such as humans). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered by one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, implantation radiation, stereotactic radiosurgery, whole-body radiation therapy, radiotherapy, and sustained or transient interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by means of a radioactive material inserted into or near a site of tumor or other proliferative tissue disease in the body. This term is intended, but not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu). Suitable radiation sources used as cytomodulation agents of this disclosure include solid and liquid forms. As a non-limiting example, the radioactive source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from a solution of any radionuclide, such as a solution of I-125 or I-131, or the radioactive fluid can be generated using a slurry containing small particles of a suitable fluid, such as Au-198 or Y-90. Furthermore, the radionuclide can be embedded in a gel or radioactive microspheres.

[0237] In some embodiments, compound A can make abnormal cells more sensitive to radiotherapy, thereby killing such cells or inhibiting their growth. Therefore, this disclosure further relates to a method for sensitizing abnormal cells in a mammal to radiotherapy, the method comprising administering to the mammal a quantity of the compound of this disclosure, the quantity of which effectively sensitizes the abnormal cells to radiotherapy. The amount of the compound in the method may be determined according to the manner used to determine the effective amount of such compounds described herein. In some embodiments, compound A can be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0238] In some embodiments, the non-pharmacological treatment is adoptive T-cell transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may 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 source of the T cells is obtained from a subject before the T cells are expanded and genetically modified. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from sites of infection, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of this disclosure, a variety 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 T cell genes are modified to express the desired protein (e.g., CAR), T cells can generally be activated and expanded using methods described, for example, in the following U.S. patents: 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 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.

[0239] In some embodiments, the compositions and methods described herein may include a combination of compound A with one or more tight junction protein-18 targets. Tight junction protein-18 targets may be administered or formulated in combination with compound A and / or any additional therapeutic agents described herein. Tight junction protein-18 (e.g., tight junction protein 18.2; CLDN18.2) has emerged as a promising target for treating 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 tissues and aberrant overexpression in a range of malignancies. Numerous 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 leads to the disruption of cell polarity, which in turn results in the exposure of the CLDN18.2 epitope on the cell surface. Although targeting monoclonal antibodies are largely unable to access CLDN18.2 within the tight junction supramolecular complex located in normal tissues, perturbations of cell polarity exposing the CLDN18.2 epitope could theoretically allow CLDN18.2 targets to bind to CLDN18.2 in malignant tissues with minimal off-target effects, making CLDN18.2 an attractive therapeutic target. In some embodiments, tight junction protein-18 targets are one or more of the following: zobetuximab, ASKB589, oxemitamab (TST001), PT886 (a bispecific antibody targeting CLDN18.2 and CD47), TJ-CD4B, CMG901 (an ADC consisting of an anti-CLDN18.2 monoclonal antibody conjugated to a cytotoxic payload of monomethylauristatin E), and CT041 (autologous T cells genetically engineered to express a CAR targeting CLDN18.2).In some embodiments, references to the term tight junction protein-18 target include any such tight junction protein-18 target disclosed in any of the following patent applications: WO2024081544, WO 2024131683, WO 2024137619, WO 2024140670, WO 2024136594, WO2023034922, WO 2023046202, WO 2022203090, WO 2022133169, WO 2022100613, WO2022256449, WO 2022136642, WO 2021155380, WO 2021129765, WO 2021011885, WO2021058000, WO WO 2021218874, WO 2021027850, WO 2020156554, WO 2020025792, WO2020114480, WO 2020211792, WO 2020239005, WO 2019219089, WO 2018157147, WO2018108106, WO 2016166122, WO 2014146778, CN 118290582, CN 118203658 and CN118286201 are all incorporated herein by reference in their entirety, including the structures of the compounds disclosed therein, which are expressly incorporated herein by reference.

[0240] In some embodiments, the therapeutic agent used in combination therapy may be a steroid. Therefore, in some embodiments, one or more additional therapies include a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, and dicovazole. (cortivazol), deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortinbutyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasolPropionate, halometasone, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, 25-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone Triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0241] Other examples of therapeutic agents that can be used in combination therapy with compound A include compounds described in the following patents: U.S. Patents 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, and international patents. Patent applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089 and WO00 / 02871.

[0242] Additional therapeutic agents can be biologics used to treat cancer or its related symptoms (e.g., cytokines such as interferon or interleukins, such as IL-2). In some embodiments, the biologics are immunoglobulin-based biologics, such as monoclonal antibodies (e.g., humanized antibodies, fully human antibodies, Fc fusion proteins, or functional fragments thereof) that activate targets to stimulate anticancer responses or antagonize antigens important for cancer. Antibody-drug conjugates are also included.

[0243] Additional therapeutic agents can be immunomodulators. For example, additional therapeutic agents can be T-cell checkpoint inhibitors. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody can be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PD-L2 (e.g., a PD-L2 / Ig fusion protein) (e.g., an inhibitory antibody, an Fc fusion, or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist 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 (e.g., an inhibitory antibody or a small molecule inhibitor).In some implementations, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies (e.g., avelumab, durvalumab, atezolizumab), pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002. Non-limiting examples of immunomodulators include the targets identified in Table 1.

[0244] Table 1: Illustrative Immunomodulatory Targets Applicable to Combination Therapies

[0245] CTLA4, cytotoxic T-lymphocyte-associated antigen 4; LAG3, lymphocyte activation gene 3; PD-1, programmed cell death protein 1; PD-L1, PD-1 ligand; TIM3, T cell membrane protein 3; VISTA, T cell activation inhibitor containing V-domain immunoglobulin (Ig); KIR, killer IgG-like receptor, APC (antigen-presenting cell); TREM2 (triggered receptor 2 expressed on myeloid cells); TGF-β (transforming growth factor β). Additional treatment agents may be anti-TIGIT antibodies, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0246] In some embodiments, the combination therapy includes 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.

[0247] Additional therapeutic agents can be those used to treat cancer or its related symptoms (e.g., cytotoxic agents, non-peptide small molecules, or other compounds that can be used to treat cancer or its related symptoms, collectively referred to as "anticancer agents"). Anticancer agents can be, for example, chemotherapy agents or targeted therapy agents.

[0248] Anticancer agents include mitosis inhibitors, insertional 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, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progesterone, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, one or more additional therapies include two or more anticancer agents. Two or more anticancer agents can be used in mixtures for combined or separate administration. Suitable dosing regimens for combination anticancer agents are known in the art and described, for example, by Saltz et al. Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al. Lancet 355(9209):1041-1047 (2000).

[0249] Other non-limiting examples of anticancer agents include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); and Iressa®. Gefitinib; alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; azacyclopropanes, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and tris(hydroxymethylmelamine); polyacetyl (especially bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189, and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin;Nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, calicheamicin γ-II and calicheamicin ω-II). (See example;) Agnew, Chem. Intl. Ed Engl.33:183-186 (1994)); dynemicin, such as dynemicin A; bisphosphonates, such as clodronate; esperamicin; neocarzinostatin chromophore and related chromogens, aclacinomysin, actinomycin, autramycin, azaserine, bleomycin, actinomycin C (cactinomycin), calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, dactinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, adriamycin (doxorubicin), N-morpholino-doxorubicin, cyano(N-morpholino)-doxorubicin, 2-pyrrololino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (e.g., mitomycin C), mycophenolic acid The following are listed as potential drug names: nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues, such as denopterin, pteropterin, and trimetrexate.Purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and fluxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenergics, such as aminoglutethimide, mitotane, and trilostane; and folic acid supplements, such as frolic acid. acid); aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate); epothilone, such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine;PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonicacid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecene, such as T-2 toxin, verracurin A, roridin A. A) and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids such as Taxol® (paclitaxel), Abraxane® (a nanoparticle formulation of paclitaxel engineered with albumin and free of polyoxyethylene hydrogenated castor oil), and Taxotere® (docetaxel); chloranbucil; tamoxifen. (Nolvadex™); raloxifene; aromatase inhibitor 4(5)-imidazole; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene (Fareston®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine®; novantrone;Teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esperamicins; capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the above.

[0250] Additional, non-restricted examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), and rituximab. Rituxan®, Taxol®, Arimidex®, ABVD, avicine, abagovomab, acridinecarboxamide, adecatumumab, 17-N-allylamino-17-demethoxygerdomylmycin, alpharadin, alvocidib, 3-aminopyridine-2-carbaldehyde thiohexacarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antitumor drugs (e.g., cell cycle nonspecific antitumor agents and other antitumor agents described herein), antitumor herbal remedies, apaziquone, atipremod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, butthionine sulfoximine, CBV(Chemotherapy), calyculin, dichloroacetic acid, discormolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, lan Laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, naproxen, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, halostazine A (salinosporamide A), sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatintetranitrate, tri(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0251] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vincristine, vinorelbine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin / actinomycin D, donomycin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, and plicamycin. Mitomycin, enzymes (e.g., L-asparaginase, which systemically metabolizes L-asparagine and removes cells that cannot synthesize asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents (e.g., nitrogen mustard (e.g., methomyl mustard, cyclophosphamide and analogues, melphalan and chlorambucil), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogues, and streptozocin), and trazenes-dacarbazinine. (DTIC), antiproliferative / antimitotic antimetabolites (e.g., folic acid analogs), pyrimidine analogs (e.g., fluorouracil, azuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole) and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, DNA binding agents (e.g., Zalypsis®), PI3K inhibitors (e.g., PI3K δ inhibitors (e.g., GS-1101 and TGR-1202), PI3K δ and γ inhibitors (e.g., CAL-130, cupanixin, apeliximab, and idelalisib); multi-kinase inhibitors (e.g., TG02 and sorafenib); hormones (e.g., estrogens) and hormone agonists, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin);BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), P13K / Akt inhibitors (e.g., pirivoxetine), PKC inhibitors (e.g., enzastaurin), FTI (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targets (e.g., MKC-3946), and cFMS inhibitors (e.g., ARRY-382).

[0252] In some embodiments, the anticancer agent is selected from methicillin, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analogue or derivative variant thereof. In some embodiments, the anticancer agent is JAB-3312.

[0253] In some implementations, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0254] In some implementations, additional therapeutic agents include 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 immunomodulatory therapies, such as immune checkpoint inhibitors. In some implementations, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0255] In some embodiments, the additional therapeutic agent is 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) inhibitor of this disclosure is used in combination with MEK inhibitors and SOS1 inhibitors. In some embodiments, the RAS(ON) inhibitor of this disclosure is used in combination with PD-L1 inhibitors and SOS1 inhibitors. In some embodiments, the RAS(ON) inhibitor of this disclosure is used in combination with PD-L1 inhibitors and SHP2 inhibitors. In some embodiments, the RAS(ON) inhibitor of this disclosure is used in combination with a MEK inhibitor and an SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer, and the treatment includes administration of a combination of the Ras inhibitor of this disclosure with a second or third therapeutic agent.

[0256] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0257] Immunotherapy includes, but is not limited to, monoclonal antibodies, immunomodulatory imides (IMiD), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1 agents, anti-PD-L1 agents, anti-CTLA4 agents, anti-LAGI agents, and anti-OX40 agents.

[0258] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs containing imide groups (drugs that regulate immune responses). IMiD drugs include thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0259] Exemplary anti-PD-1 antibodies and their methods of use 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 also described elsewhere in this article.

[0260] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the 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, EP The anti-GITR antibodies described in U.S. Patent Nos. 1947183, 7,812,135, 8,388,967, 8,591,886, 7,618,632, EP1866339, WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0261] Another example of a therapeutic agent that can be used in combination with compound A is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions synthesized in vitro, antibodies, antigen-binding domains, radionuclides, and combinations and conjugates thereof. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally, can be used to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), thereby promoting cell death or arresting cell growth. In some embodiments, one or more additional therapies include an anti-angiogenic agent.

[0262] Anti-angiogenic agents can be MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, tesiromixol (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578 and US20090012085, as well as U.S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are inhibitors with very low or no MMP-1 inhibitory activity. More preferably are inhibitors that selectively inhibit MMP-2 or AMP-9 relative 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 include AG-3340, RO 32-3555, and RS 13-0830.

[0263] Other exemplary antiangiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding domains that specifically bind to kinase domain receptors), EGFR inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to EGFR), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen-binding domains that specifically bind to Angle and Ang2 or their receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to Tie2 kinase). Other anti-angiogenic agents include Camppath, IL-8, β-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., specifically binding antibody or antigen-binding domains, or soluble TWEAK receptor antagonists; see US6,727,225), and ADAM unintegrin domains that antagonize the binding of integrins to their ligands (US...). 2002 / 0042368), specifically binding anti-eph receptor or anti-pterygium antibody or antigen-binding region (US Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124 and members of their patent families), and anti-PDGF-BB antagonists (e.g., specifically binding antibody or antigen-binding region), as well as antibodies or antigen-binding regions specifically binding to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions specifically binding to PDGFR kinases). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US5892112); emaxanib (Pfizer, USA, US5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland);Anecrolave ​​acetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands), DAC anti-angiogenic agent (ConjuChem, Canada); Angiocidin (InKinePharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); 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); 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, JP 02233610); Platelet-4 (RepliGen, USA, EP 407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL647 (Exelixis, USA); second-generation α5β3 integrin MAb (Applied Molecular Evolution, USA and Medlmmune, USA); enzastaurin hydrochloride (Lilly, USA);CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived anti-angiogenic agents (XOMA, USA); PI 88 (Progen, Australia); Cilengiptide (Merck KGaA, Germany; Munich Technical University, Germany; Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); 2-Methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); Vataranib (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue factor pathway inhibitor (EntreMed, USA); Pinn (Gilead Sciences, USA); Xanthorrhizol (Yonsei University, South Korea); Gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California, San Diego, USA); PX 478 (ProlX, USA); METASTATIN (EntreMed, USA); Troponin I (Harvard University, USA);SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); atemod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); angiogenesis vaccine (EntreMed, USA); urokinase plasminogen activator inhibitor (Dendreon, USA); oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); InKine (USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); Drug delivery system, intraocular 2-methoxyestradiol; Anginex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-α inhibitors; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA);YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); KDR Mab (ImClone Systems, USA); α5β Mab (Protein Design, USA); KDR kinase inhibitors (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); cobretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA; Takeda, Japan; and TAP, USA); AG 13925 (Agouron, USA); tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA) CV 247 (Ivy Medical, UK); CKD 732 (Chong KunDang, South Korea); Irsogladine (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); Squalamine (Genaera, USA); RPI 4610 (Sirna, USA); Heparinase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); and Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan);VE-cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck&Co, USA); Tie-2 ligand (Regeneron, USA); and thromboprotein 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0264] Other examples of therapeutic agents that can be used in combination with compound A include agents that specifically bind to and inhibit the activity of growth factors (e.g., antibodies, antigen-binding domains, or soluble receptors), such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding domains that specifically bind to receptor c-Met.

[0265] Another example of a therapeutic agent that can be used in combination with compound A is an antitumor agent. In some embodiments, one or more additional therapies include an antitumor agent. Non-limiting examples of antitumor agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, aifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, and DA. 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac (HIT), interferon-alpha, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, beta-epoetin beta), etoposide phosphate, exemestane, escitaline, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, formustin, gallium nitrate, gemcitabine, gemtuzumab, oxazolidinZogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronicacid, idarubicin, imiquimod, interferon α, natural interferon α, interferon α-2, interferon α-2a, interferon α-2b, interferon α-Nl, interferon α-n3, compound interferon-1, natural interferon α, interferon β, interferon β-la, interferon β-lb, interferon γ, natural interferon γ-la, interferon γ-lb, interleukin-1 β, iobenguane, irinotecan, isoladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoxone, dibromoceroxyl, mitoxone, molgramostim, nafarelin, naloxone + Pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, new erythropoietin, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, pegylated interferon alpha-2b, pentosan polysulfatesodium, pentostatin, picibanil, pirubicin, rabbit anti-thymocyte polyclonal antibody, pegylated interferon alpha-2a, porfimer sodiumsodium), raloxifene, raltitrexed, rasburiembodiment, rhenium hydroxyethylphosphonate Re 186, retinamide (RII), rituximab, romurtide, samarium lexidronam (153 Sm), sargramostim, cizonan, sobuzoxane, sonermin, strontium chloride-89, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alpha Alfa, topotecan, toremifene, tositumomab-iodine131, trastuzumab, treosulfan, tretinoin, tralosterol, trimethoprim, triptorelin, natural tumor necrosis factor alpha, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysis product vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diazinon, EL 532 (Elan), EM 800 (Endorecherche), enuracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomabTiuxetan), Ilomastat, IM 862 (Cytran), Interleukin-2, Iproxifene, LDI 200 (Milkhaus), Leristatin, Lintuzumab, CA 125 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 (Techniclone), Polymorphic Epithelial Mucin-Yttrium-90 MAb (Antisoma), Marimastat, Menogaril, Mitumomab, Motexafin Gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysis product vaccine (New York Medical Center) College, viral melanoma cell lysis product vaccine (Royal Newcastle Hospital), or valspodar.

[0266] Additional examples of therapeutic agents that can be used in combination with compound A include ipilimumab (Yervoy®); trimemumab; 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; and anti-OX40 (Providence Health). Services); huMAbOX40L; atacivib; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); trastuzumab (Kadcyla®); eylea®; alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); basiliximab Simulect®; Benlysta®; Brentuximab vedotin (Adcetris®); Canakinumab (Ilaris®); Cimzia® (certolizumab pegol); Zenapax®; Daratumumab (Darzalex®); Prolia®; Soliris®; Raptiva®; Gemtuzumab ozogamicin (Mylotarg®); Golimumab (Simponi®); Ibritumomab tiuxetan) (Zevalin®); infliximab (Remicade®);Motavizumab (Numax®); Natalizumab (Tysabri®); Obinutuzumab (Gazyva®); Ofatumumab (Arzerra®); Omalizumab (Xolair®); Palivizumab (Synagis®); Pertuzumab (Perjeta®); Pertuzumab (Perjeta®); Ranibizumab (Lucentis®); Raxibacumab (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.

[0267] Depending on the condition being treated, the compounds described herein may be used in combination with the agents disclosed herein or other suitable agents. Therefore, in some embodiments, one or more compounds of this disclosure will be co-administered with other therapies as described herein. When used as a combination therapy, the compounds described herein may be administered simultaneously or separately with a second agent. This combination administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. In other words, the compounds described herein and any of the agents described herein may 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 may be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, the compounds of this disclosure may be administered, followed by any of the therapies described herein, or vice versa. In some embodiments of the separate administration regimen, the compounds of the present invention and any of the therapies described herein may be administered minutes, hours, or days apart.

[0268] In some embodiments of any of the methods described herein, a first treatment and one or more additional treatments are administered simultaneously or sequentially in any order. The first treatment may be administered immediately before or after the administration of one or more additional treatments, at most 1 hour, at most 2 hours, at most 3 hours, at most 4 hours, at most 5 hours, at most 6 hours, at most 7 hours, at most 8 hours, at most 9 hours, at most 10 hours, at most 11 hours, at most 12 hours, at most 13 hours, at most 14 hours, at most 16 hours, at most 17 hours, at most 18 hours, at most 19 hours, at most 20 hours, at most 21 hours, at most 22 hours, at most 23 hours, at most 24 hours, or at most 1-7 days, 1-14 days, 1-21 days, or 1-30 days.

[0269] A further feature of this disclosure is a medicine box comprising (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the present invention), and (b) a packaging insert with instructions on performing any of the methods described herein. In some embodiments, the medicine box comprises (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the present invention), (b) one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents), and (c) a packaging insert with instructions on performing any of the methods described herein.

[0270] Since one aspect of this disclosure covers the treatment of diseases or their associated symptoms with combinations of separately administerable pharmaceutically active compounds, the invention further relates to the combination of separate pharmaceutical compositions in the form of a pillbox. The pillbox may contain two separate pharmaceutical compositions: the compound of the present invention and one or more additional therapies. The pillbox may include a container for containing the separate compositions, such as a dispensing vial or a dispenser foil package. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the pillbox may include instructions on the use of the separate components. The pillbox form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dose intervals, or when a prescribing healthcare professional wishes to adjust the individual components in the combination.

[0271] Implementation Plan Implementation Scheme 1: A method for treating cancer in a human subject in need, the method comprising orally administering to the subject a total daily dose of compound A of 50 mg to 800 mg: (Compound A) Or its pharmaceutically acceptable salt.

[0272] Implementation Scheme 2: The method of Implementation Scheme 1, wherein the method comprises administering compound A to the subject at a total daily dose of 60 mg to 800 mg.

[0273] Implementation Scheme 3: The method of Implementation Scheme 1, wherein the method comprises administering the subject a total daily dose of compound A of 70 mg to 800 mg.

[0274] Implementation Scheme 4: The method of Implementation Scheme 1, wherein the method comprises administering 80 mg to 500 mg of compound A to the subject.

[0275] Implementation Scheme 5: The method of Implementation Scheme 1, wherein the method comprises administering compound A to the subject at a total daily dose of 100 mg to 800 mg.

[0276] Implementation Scheme 6: The method of Implementation Scheme 1, wherein the method comprises administering compound A to the subject at a total daily dose of 120 mg to 800 mg.

[0277] Implementation Scheme 7: The method of Implementation Scheme 1, wherein the method comprises administering compound A to the subject at a total daily dose of 160 mg to 800 mg.

[0278] Implementation Scheme 8: The method of Implementation Scheme 1, wherein the method comprises administering compound A to the subject at a total daily dose of 200 mg to 800 mg.

[0279] Implementation Scheme 9: The method of Implementation Scheme 1, wherein the method comprises administering compound A to the subject at a total daily dose of 250 mg to 800 mg.

[0280] Implementation Scheme 10: The method of Implementation Scheme 1, wherein the method comprises administering to the subject a total daily dose of compound A of 300 mg to 800 mg.

[0281] Implementation Scheme 11: The method of Implementation Scheme 1, wherein the method comprises administering compound A to the subject at a total daily dose of 350 mg to 800 mg.

[0282] Implementation Scheme 12: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 400 mg to 800 mg to the subject.

[0283] Implementation Scheme 13: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 450 mg to 800 mg to the subject.

[0284] Implementation Scheme 14: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 500 mg to 800 mg to the subject.

[0285] Implementation Scheme 15: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 550 mg to 800 mg to the subject.

[0286] Implementation Scheme 16: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 600 mg to 800 mg to the subject.

[0287] Implementation Scheme 17: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 650 mg to 800 mg to the subject.

[0288] Implementation Scheme 18: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 700 mg to 800 mg to the subject.

[0289] Implementation Scheme 19: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 750 mg to 800 mg to the subject.

[0290] Implementation Scheme 20: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 750 mg to 800 mg to the subject.

[0291] Implementation Scheme 21: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 750 mg to 800 mg to the subject.

[0292] Implementation Scheme 22: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 225 mg to 575 mg to the subject.

[0293] Implementation Scheme 23: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 250 mg to 550 mg to the subject.

[0294] Implementation Scheme 24: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 275 mg to 525 mg to the subject.

[0295] Implementation Scheme 25: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 300 mg to 500 mg to the subject.

[0296] Implementation Scheme 26: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 325 mg to 475 mg to the subject.

[0297] Implementation Scheme 27: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 350 mg to 450 mg to the subject.

[0298] Implementation Scheme 27: The method of Implementation Scheme 1, wherein the method includes administering a total daily dose of 375 mg to 425 mg to the subject.

[0299] Implementation Scheme 28: The method of any one of Implementation Schemes 1 to 27, wherein compound A is applied once or twice daily.

[0300] Implementation Scheme 29: The method of Implementation Scheme 1 or 2, wherein the method comprises administering 60 mg of compound A to the subject.

[0301] Implementation Scheme 30: The method of any one of Implementation Schemes 1 to 3, wherein the method comprises administering 70 mg of compound A to the subject.

[0302] Implementation Scheme 31: The method of any one of Implementation Schemes 1 to 4, wherein the method comprises administering 80 mg of compound A to the subject.

[0303] Implementation Scheme 32: The method of any one of Implementation Schemes 1 to 5, wherein the method comprises administering 100 mg of compound A to the subject.

[0304] Implementation Scheme 33: The method of any one of Implementation Schemes 1 to 6, wherein the method comprises administering 120 mg of compound A to the subject.

[0305] Implementation Scheme 34: The method of any one of Implementation Schemes 1 to 6, wherein the method comprises administering 160 mg of compound A to the subject.

[0306] Implementation Scheme 35: The method of any one of Implementation Schemes 1 to 7, wherein the method comprises administering 200 mg of compound A to the subject.

[0307] Implementation Scheme 36: The method of any one of Implementation Schemes 1 to 8, wherein the method comprises administering 250 mg of compound A to the subject.

[0308] Implementation Scheme 37: The method of any one of Implementation Schemes 1 to 9, wherein the method comprises administering 300 mg of compound A to the subject.

[0309] Implementation Scheme 38: The method of any one of Implementation Schemes 1 to 10, wherein the method comprises administering 350 mg of compound A to the subject.

[0310] Implementation Scheme 39: The method of any one of Implementation Schemes 1 to 11, wherein the method comprises administering 400 mg of compound A to the subject.

[0311] Implementation Scheme 40: The method of any one of Implementation Schemes 1 to 12, wherein the method comprises administering 450 mg of compound A to the subject.

[0312] Implementation Scheme 41: The method of any one of Implementation Schemes 1 to 13, wherein the method comprises administering 500 mg of compound A to the subject.

[0313] Implementation Scheme 42: The method of any one of Implementation Schemes 1 to 14, wherein the method comprises administering 550 mg of compound A to the subject.

[0314] Implementation Scheme 43: The method of any one of Implementation Schemes 1 to 15, wherein the method comprises administering 600 mg of compound A to the subject.

[0315] Implementation Scheme 44: The method of any one of Implementation Schemes 1 to 16, wherein the method comprises administering 650 mg of compound A to the subject.

[0316] Implementation Scheme 45: The method of any one of Implementation Schemes 1 to 17, wherein the method comprises administering 700 mg of compound A to the subject.

[0317] Implementation Scheme 46: The method of any one of Implementation Schemes 1 to 18, wherein the method comprises administering 750 mg of compound A to the subject.

[0318] Implementation Scheme 47: The method of any one of Implementation Schemes 1 to 18, wherein the method comprises administering 800 mg of compound A to the subject.

[0319] Implementation Scheme 48: The method of Implementation Scheme 1, wherein the method comprises administering 175 mg to 325 mg of compound A twice daily.

[0320] Implementation Scheme 49: The method of Implementation Scheme 1, wherein the method comprises administering 200 mg to 300 mg of compound A twice daily.

[0321] Implementation Scheme 50: The method of Implementation Scheme 1, wherein the method comprises administering 225 mg to 275 mg of compound A twice daily.

[0322] Implementation Scheme 51: The method of Implementation Scheme 1, wherein the method comprises administering 200 mg of compound A twice daily.

[0323] Implementation Scheme 52: The method of Implementation Scheme 1, wherein the method comprises administering 300 mg of compound A twice daily.

[0324] Implementation Scheme 53: The method of Implementation Scheme 1, wherein the method comprises administering 400 mg of compound A twice daily by BID.

[0325] Implementation scheme 54: The method of any one of implementation schemes 1 to 53, wherein compound A is administered to the subject daily on one or more days per week.

[0326] Implementation scheme 55: The method of any one of implementation schemes 1 to 53, wherein compound A is administered to the subject once daily on days 1, 2, 3, 4, 5, 6 and 7 of each 7-day period.

[0327] Implementation Scheme 56: The method of any one of Implementation Schemes 1 to 55, wherein the cancer contains a RAS G12C mutation.

[0328] Implementation Scheme 57: The method of Implementation Scheme 56, wherein the cancer is pancreatic cancer.

[0329] Implementation scheme 58: The method of implementation scheme 56, wherein the cancer is lung cancer.

[0330] Implementation Scheme 59: The method of Implementation Scheme 56, wherein the cancer is colorectal cancer.

[0331] Implementation Scheme 60: The method of any one of Implementation Schemes 1 to 59, wherein the method further includes the application of an additional therapeutic agent.

[0332] Implementation Scheme 61: The method of Implementation Scheme 60, wherein the additional therapeutic agent is a pan-KRAS inhibitor.

[0333] Implementation Scheme 62: The method of Implementation Scheme 60, wherein the additional therapeutic agent is a KRASG12C(OFF) inhibitor.

[0334] Implementation Scheme 63: The method of Implementation Scheme 60, wherein the additional therapeutic agent is a multiselective RAS(ON) inhibitor.

[0335] Implementation Scheme 64: The method of Implementation Scheme 60, wherein the additional therapeutic agent comprises an SHP2 inhibitor and a PD-L1 inhibitor.

[0336] Implementation Scheme 65: The method of Implementation Scheme 60, wherein the additional therapy comprises a second RAS inhibitor and a PD-L1 inhibitor.

[0337] Implementation Scheme 66: The method of Implementation Scheme 60, wherein the additional therapy is pembrolizumab or a biosimilar thereof.

[0338] Implementation Scheme 67: The method of Implementation Scheme 60, wherein the additional therapy is cetuximab or a biosimilar thereof.

[0339] Implementation Scheme 68: A method of treating a subject with cancer containing a RAS G12C mutation, the method comprising oral administration of a total daily dose of compound A of 200 mg to 800 mg, wherein the subject is given compound A twice daily.

[0340] Implementation Scheme 69: The method of Implementation Scheme 68, wherein the method further includes screening or monitoring the subject's modulated cardiac function.

[0341] Implementation scheme 70: The method of implementation scheme 68, wherein the subject does not have congenital long QT syndrome or does not have QTc prolongation.

[0342] Implementation Scheme 71: The method of Implementation Scheme 68, wherein the subject has stopped using or avoided using products known to prolong the QTc interval.

[0343] Implementation Scheme 72: The method of Implementation Scheme 68, wherein changes in the QTc interval were detected during treatment with compound A.

[0344] Implementation Scheme 73: The method of Implementation Scheme 72, wherein the change in the QTc interval is a QTc absolute value greater than 500 ms or an increase of more than 60 ms from the baseline.

[0345] Implementation Scheme 74: The method of Implementation Scheme 72 or 73, wherein the method includes pausing the administration of compound A for a period of time sufficient to reduce the QTc interval to less than about 481 ms or to restore it to baseline.

[0346] Implementation Scheme 75: The method of Implementation Scheme 74, wherein the method includes reducing the dose of compound A.

[0347] Implementation Scheme 76: The method of any one of Implementation Schemes 1 to 75, wherein the subject has previously undergone at least one or more systemic cancer therapies.

[0348] Implementation Scheme 77: The method of any one of Implementation Schemes 68 to 76, wherein the cancer is NSCLC.

[0349] Implementation Scheme 78: The method of any one of Implementation Schemes 68 to 76, wherein the cancer is CRC.

[0350] Implementation Scheme 79: The method of any one of Implementation Schemes 68-78, wherein the subject has previously used KRAS G12C She had been treated with (OFF) inhibitors.

[0351] Implementation Scheme 80: The method of any one of Implementation Schemes 68-78, wherein the subject has not previously used KRAS G12C She had been treated with (OFF) inhibitors.

[0352] Implementation scheme 81: The method of any one of implementation schemes 1 to 80, wherein compound A is not administered with food.

[0353] Implementation scheme 82: The method of any one of implementation schemes 1 to 80, wherein the subject does not eat for at least 4 hours after administration of compound A.

[0354] Implementation scheme 83: The method of any one of implementation schemes 1 to 80, wherein the subject has not eaten for at least 8 hours before administration of compound A.

[0355] Implementation Scheme 84: The method of any one of Implementation Schemes 1 to 80, wherein the subject has not eaten for at least 4 hours before administration of compound A and the subject has not eaten for at least 4 hours after administration of compound A.

[0356] Implementation Scheme 85: The method of any one of Implementation Schemes 1 to 80, wherein the subject is in a fasting state when compound A is administered.

[0357] Implementation Scheme 86: The method of Implementation Scheme 85, wherein the subject does not drink water for 1 hour before and / or 1 hour after administration of compound A.

[0358] Example This disclosure will be further illustrated by the following examples, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the provided examples are intended to illustrate certain implementations and are not intended to limit the scope of this disclosure. It should also be understood that various other implementations, modifications, and equivalents that may be conceived by those skilled in the art can be utilized without departing from the spirit of this disclosure or the scope of the appended claims.

[0359] Example 1. Suffering from late-stage disease KRAS G12C Study design for compound A monotherapy in subjects with mutant solid tumors As described in this article, compound A is a potent, covalent, ternary complex, orally bioavailable RAS(ON) inhibitor, effective against mutant RAS. G12C The active GTP binding state of compound A is selective. Compound A binds to the intracellular protein cyclophilic protein A (CypA), which is ubiquitous and highly expressed in both normal tissues and tumors, with evidence suggesting particularly high expression in tumors and potential involvement in malignant transformation. The binding of compound A to CypA forms an inhibitory binary complex, which subsequently binds to KRAS. G12C (ON) binding forms a stable ternary complex, leading to compound A's influence on KRAS. G12CThe unique Cys-12 residues undergo irreversible covalent modification. This ternary complex is formed by disrupting KRAS. G12C T...

Claims

1. A method of treating cancer in a human subject in need, the method comprising orally administering to the subject a total daily dose of compound A of 50 mg to 800 mg: Compound A.

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

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

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

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

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

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

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

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

10. The method of any one of claims 1 to 9, wherein compound A is applied once daily or twice daily.

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

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

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

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

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

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

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

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

19. The method of any one of claims 1 to 18, wherein compound A is applied once, twice, three times, four times, five times, six times, or seven times per week.

20. The method of any one of claims 1 to 19, wherein the subject is given 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.

21. The method of any one of claims 1 to 19, wherein compound A is administered in treatment cycles and each 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.

22. The method of claim 21, wherein the subject undergoes one, two, three or more treatment cycles.

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

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

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

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

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

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

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

30. The method of any one of claims 1 to 29, wherein the method further comprises administering an additional therapeutic agent.

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

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

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

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

35. The method of claim 34, wherein the method further comprises screening or monitoring the subject's modulated cardiac function.

36. The method of claim 35, wherein the subject does not have congenital long QT syndrome or QTc prolongation.

37. The method of claim 35, wherein the subject has stopped using or avoided using products known to prolong the QTc interval.

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

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

40. The method of claim 38 or 39, wherein the method comprises pausing the administration of compound A for a period of time sufficient to reduce the QTc interval to less than about 481 ms or to restore it to baseline.

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

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

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

44. The method of claim 42 or 43, wherein the subject has previously received at least one cancer therapy.

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

46. The method of any one of claims 42 to 45, wherein the prior KRAS G12C (OFF) inhibitor.

47. The method of any one of claims 42 to 45, wherein the subject has not received treatment with a KRAS G12C (OFF) inhibitor therapy.

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

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

50. The method of claim 48 or 49, wherein the subject has previously received at least one cancer therapy.

51. The method of any one of claims 48 to 50, wherein the subject has not received treatment with a KRASG12C(OFF) inhibitor.

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