Combination therapy for RAS-related disorders or conditions

Abstract

This disclosure relates to combination therapies for treating RAS-related diseases or disorders (e.g., cancer). In particular, this disclosure relates to methods for treating RAS-related diseases or disorders in subjects requiring treatment for such diseases or disorders, comprising administering a therapeutically effective dose of a RAS(ON) inhibitor to the subject in combination with one or more additional therapeutic agents, a pharmaceutical composition comprising a therapeutically effective dose of a RAS(ON) inhibitor, a kit comprising the composition, and a method of use thereof.

Description

Technical Field

[0001] The present disclosure relates to combination therapies useful for the treatment of abnormal RAS signaling (e.g., the treatment of RAS-dependent cancers). In certain embodiments, provided herein are compositions comprising a therapeutically effective combination comprising a RAS(ON) inhibitor, pharmaceutical compositions comprising a combination therapy, and methods of using them for the treatment of diseases or disorders having modulated RAS activity.

Background Art

[0002] It is well established in the literature that RAS proteins (K-RAS, H-RAS, and N-RAS) play an essential role in various RAS-related diseases such as cancer, RASopathies, and neuropathies, and mutations in the RAS gene or its regulators constitutively activate the RAS protein and thus represent suitable targets for therapy. Indeed, mutations in the RAS protein account for approximately 30% of all human cancers in the United States, many of which are lethal. Dysregulation of the RAS protein by mutant activation, overexpression, or upstream activation is common in human tumors, and mutant activation of RAS is frequently found in human cancers. For example, mutant activation of codon 12 in the RAS protein inhibits both the GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of RAS mutant proteins into the "on" (GTP-bound) state (RAS(ON)) and functioning by driving oncogenic MAPK signaling. In particular, RAS exhibits picomolar affinity for GTP, enabling RAS to be activated even in the presence of low concentrations of this nucleotide. Mutations in codon 13 of RAS (e.g., G13D), and codon 61 (e.g., Q61K) also confer oncogenic activity in some cancers.

[0003] Despite decades of extensive drug discovery efforts targeting abnormal RAS signaling, the existence of acquired and adaptive resistance mechanisms associated with RAS mutant cancers makes it difficult to achieve complete and durable responses. Further efforts are needed to identify additional compositions, including compositions with combinations of therapeutic agents, for targeting RAS-driven diseases and disorders. SUMMARY OF THE INVENTION

[0004] The present disclosure provides compositions and uses thereof for treating RAS-related diseases or disorders (e.g., cancer) comprising a RAS(ON) inhibitor and one or more additional therapeutic agents. The present disclosure is based, at least in part, on the observation that RAS-related diseases or disorders, such as cancer, can be treated with a combination of i) one or more RAS(ON) inhibitors, and ii) one or more additional therapeutic agents. In various embodiments disclosed herein, RAS-related diseases or disorders (e.g., cancer) are resistant to monotherapy with the therapeutic agents disclosed herein.

[0005] In one aspect, the present disclosure provides a method of treating cancer in a subject that needs treatment for cancer, the method generally comprising administering to the subject a therapeutically effective amount of a combination comprising i) a RAS(ON) inhibitor, and ii) one or more additional therapeutic agents.

[0006] In another aspect, the present disclosure provides a method of treating a RAS-related disease or disorder in a subject that needs treatment for the RAS-related disease or disorder, the method generally comprising administering to the subject a therapeutically effective amount of a combination comprising i) a RAS(ON) inhibitor, and ii) one or more additional therapeutic agents.

[0007] In yet another aspect, the present disclosure provides a method of modulating RAS activity and the activity of one or more target proteins in a cell, the method generally comprising administering to the cell an effective amount of a combination comprising i) a RAS(ON) inhibitor, and ii) one or more additional therapeutic agents, wherein the one or more additional therapeutic agents modulate the activity of one or more target proteins.

[0008] In further different embodiments, the Disclosure provides a method for inhibiting RAS activity and the activity of one or more target proteins in cells, the method generally comprising administering to cells an effective amount combination of i) a RAS(ON) inhibitor and ii) one or more additional therapeutic agents, the one or more additional therapeutic agents modulating the activity of one or more target proteins.

[0009] In each of the above embodiments, the additional therapeutic agent may be a second different RAS(ON) inhibitor (e.g., a RAS(ON) variant-selective inhibitor or a RAS(ON) multiselective inhibitor). In each of the above embodiments, the RAS(ON) inhibitor may be selected from the RAS(ON) inhibitors described herein, for example, those disclosed in Section I(A).

[0010] In some embodiments, one or more additional therapeutic agents are RAS / MAPK pathway inhibitors, kinase inhibitors, receptor tyrosine kinase inhibitors, PI3K / mTOR pathway inhibitors, DNA damage response inhibitors, cell cycle inhibitors, anti-apoptotic protein inhibitors, autophagy inhibitors, macropinocytosis inhibitors, Wnt / beta-catenin pathway inhibitors, JAK / STAT pathway inhibitors, epigenetic modulators, immunotherapies, farnesyltransferase inhibitors, TGF-beta inhibitors, HSP90 inhibitors, GPX4 inhibitors, NRF2 inhibitors, TEAD inhibitors, NOTCH inhibitors, gamma-secretase inhibitors, Hedgehog inhibitors, chemotherapeutic agents, proteasome inhibitors, or any combination thereof.

[0011] In some embodiments, the RAS / MAPK pathway inhibitor is a RAS(OFF) inhibitor, SOS1 inhibitor, SHP2 inhibitor, MEK inhibitor, RAF inhibitor, ERK inhibitor, MAPK inhibitor, or any combination thereof.

[0012] In some embodiments, the RAS(OFF) inhibitor is selected from the RAS(OFF) inhibitors described herein, for example, those disclosed in Section I(b)(i). In some embodiments, the SOS1 inhibitor is RMC-5845, RMC-4948, RMC-0331, BI-1701963, BI-3406, SDR5, MRTX0902, BAY-293, or any combination thereof.

[0013] In some embodiments, the SHP2 inhibitor is SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, BBP-398, or any combination thereof.

[0014] In some embodiments, the MEK inhibitor is pimacertib, selumetinib, cobimetinib, trametinib, binimetinib, or any combination thereof. In some embodiments, the RAF inhibitor is VS-6766, IK-595, vemurafenib, dabrafenib, and encorafenib, or any combination thereof.

[0015] In some embodiments, the ERK inhibitor is ASTX-029, I-75, or a combination thereof. In some embodiments, the MAPK inhibitor is tilpisertib (GS-4875), neflamapidmod (VX-745), or a combination thereof.

[0016] In some embodiments, the kinase inhibitor is a PKA inhibitor, FAK inhibitor, ROCK inhibitor, MSK1 inhibitor, RSK inhibitor, ALK inhibitor, or any combination thereof. In some embodiments, the PKA inhibitor is H89. In some embodiments, the FAK inhibitor is BI853520, defactinib, GSK2256098, PF-00562271, VS-4718, or any combination thereof. In some embodiments, the ROCK inhibitor is GSK269962A. In some embodiments, the MSK1 inhibitor is SB-747651A, SB747651A, Ro320432, CGP57380, GSK2830371, SR1664, LY-3214996, PFI-4, MSC-2363318A, AS601245, or any combination thereof. In some embodiments, the RSK inhibitor is BI-D1870, LJH685, SL0101-1, FMK, BRD7389, BIX02565, LJI308, LJI308-S, LJI308-1, LJH685-S, or any combination thereof. In some embodiments, the ALK inhibitor is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib (X-396), TAE684, ASP3026, TPX-0131, LDK378 (ceritinib analog), CEP-37440, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, AP26113, or any combination thereof.

[0017] In some embodiments, the receptor tyrosine kinase inhibitor is an EGFR inhibitor, HER2 inhibitor, MET inhibitor, AXL inhibitor, IGFR inhibitor, RET inhibitor, ROS1 inhibitor, PDGFR inhibitor, FGFR inhibitor, VEGF inhibitor, or any combination thereof.

[0018] In some embodiments, the EGFR inhibitor is osimertinib, cetuximab, gefitinib (Iressa), erlotinib (Tarceva), razertinib, afatinib (Girotrif), or any combination thereof. In some embodiments, the HER2 inhibitor is tucatinib. In some embodiments, the MET inhibitor is crizotinib (Zalkoli), cabozantinib (Cometriq, Cabometyx), capmatinib (Tabrecta), tepotinib (Tepmetco), savolitinib (Volitinib), onartuzumab (MetMab), foretinib (GSK1363089), MGCD-265 (Amvatinib), SU11274, SU5416, or any combination thereof. In some embodiments, the AXL inhibitor is vemcentib, BGB324, R428, SGI-7079, TP-0903, BMS-777607, UNC2025, TP-0903, or any combination thereof. In some embodiments, the IGFR inhibitor is lincitinib, AXL1717, OSI-906 (lincitinib), BMS-754807, BI836845, AZ12253801, PQIP (pyrrolo[1,2-a]quinoxaline), NVP-AEW541, or any combination thereof. In some embodiments, the RET inhibitor is pralcetinib, serpercatinib (LOXO-292), BLU-667, RXDX-105, TPX-0046, GSK3179106, molidastat (BAY85-3934), RPI-1 (Retrofin), or any combination thereof. In some embodiments, the ROS1 inhibitor is taretrectinib, DS-6051b, TPX-0131, GZD824, PF-06463922, or any combination thereof. In some embodiments, the PDGFR inhibitor is CP-673451, imatinib, nintedanib (Ofev), sunitinib (Stent), pazopanib (Botrian), regorafenib (Stivarga), dasatinib (Sprycel), or any combination thereof.In some embodiments, FGFR is futivatinib (TAK-659), erdafitinib (Varvasa), infiglatinib (Truseltiq), Debio1347, and logaratinib (BAY1163877), or any combination thereof. In some embodiments, VEGF inhibitor is bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, pazopanib, or any combination thereof.

[0019] In some embodiments, the PI3K / mTOR pathway inhibitor is a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, an MNK inhibitor, an eIF4 inhibitor, or any combination thereof.

[0020] In some embodiments, the PI3K inhibitor is alpelisib, copanlisib, or a combination thereof. In some embodiments, the AKT inhibitor is ipatasertib, GSK-2141795, Akt-1-1, Akt-1-1,2, 1-H-imidazo[4,5-c]pyridinyl derivatives, indole-3-carbinol or its derivatives, perifosine, phosphatidylinositol ether lipid analogs, trisirivine, or any combination thereof. In some embodiments, the mTOR inhibitor is RMC-5552, PI-103, PP242, PP30, Torin1, FKBP12 enhancer, 4H-1-benzopyran-4-one derivative, rapamycin (sirolimus), rapalog, temsirolimus, everolimus, ridafololimus, AP23464, AP23841, 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (CC1779), 40-epi-(tetrazolito)-rapamycin (ABT578), 32-deoxorapamycin, 16-pentinyloxy-32(S)-dihydrorapanisin, phosphorus-containing rapamycin derivatives, or any combination thereof. In some embodiments, the MNK inhibitor is tomibocertib (eFT508), CGP57380, and SEL201, or any combination thereof. In some embodiments, the eIF4 inhibitor is an eIF4A inhibitor or an eIF4G inhibitor. In some embodiments, the eIF4A inhibitor is zotatifine (eFT226), silvestrol, patheamine A, locagrate, or any combination thereof. In some embodiments, the eIF4G inhibitor is patheamine A, hypristanol, or any combination thereof.

[0021] In some embodiments, the DNA damage response inhibitor is a Wee1 inhibitor, a CHK inhibitor, an ATM inhibitor, an ATR inhibitor, a PARP inhibitor, a DNA-PK inhibitor, or any combination thereof. In some embodiments, the Wee1 inhibitor is adavocertib, AZD1775, ZNL-02-096, MK-1775, or any combination thereof. In some embodiments, the CHK inhibitor is a CHK1 or CHK2 inhibitor. In some embodiments, the CHK inhibitor is ravcertib, LY2606368, GDC-0575, MK-8776, or any combination thereof. In some embodiments, the ATM inhibitor is M4076, AZD0156, KU-60019, VE-821, or any combination thereof. In some embodiments, the ATR inhibitor is ceraracertib, VX-970, AZD6738, BAY1895344, or any combination thereof. In some embodiments, the PARP inhibitor is olaparib, lucaparib, niraparib, veliparib (ABT-888), or any combination thereof. In some embodiments, the DNA-PK inhibitor is NU7441, AZD7648, VX-984, M3814, CC-115, SCR7, or any combination thereof.

[0022] In some embodiments, the cell cycle inhibitor is a CDK inhibitor, an aurora kinase inhibitor, a PLK inhibitor, a KSP inhibitor, or any combination thereof. In some embodiments, the CDK inhibitor is a CDK2 inhibitor, a CDK4 / 6 inhibitor, a CDK7 inhibitor, or a CDK9 inhibitor, or any combination thereof. In some embodiments, the CDK inhibitor is cericiclib, UCN-01, P1446A-05, PD-0332991, dynacyclib, P27-00, AT-7519, RGB286638, SCH727965, AZD4573, or any combination thereof. In some embodiments, the aurora kinase inhibitor is palbociclib, ribociclib, abemaciclib, aricertib, danucertib, valacertib, MLN8237, or any combination thereof. In some embodiments, the PLK inhibitor is volasertib, onvancertib, BI2536, GSK461364, or any combination thereof. In some embodiments, the KSP inhibitor is SB743921, monastrole, S-trityl-L-cysteine ​​(STLC), filanesib (ARRY-520), AMG650, BTB-1, K03861, SJ000291942, or any combination thereof. In some embodiments, the anti-apoptotic inhibitor is a Bcl inhibitor, XIAP inhibitor, survivorin inhibitor, Mcl-1 inhibitor, or FLIP inhibitor, or any combination thereof. In some embodiments, the Bcl inhibitor is ABT-263, venetoclax (Veneclexta), navitoclax (ABT-263), A-1331852, S63845, AT-101, or any combination thereof. In some embodiments, the Mcl-1 inhibitor is AMG-176, MIK665, S63845, or any combination thereof.

[0023] In some embodiments, the autophagy inhibitor is chloroquine, 3-methyladenine, hydroxychloroquine, spoutin-1, SAR405, bafilomycin A1, 5-amino-4-imidazole carboxamido riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins, cAMP analogs, LY204002, N6-mercaptopurine riboside, vinblastine, ULK1 inhibitors, VPS inhibitors, or any combination thereof. In some embodiments, the ULK1 inhibitor is a ULK1 / 2 inhibitor. In some embodiments, the ULK inhibitor is ULK-101, MRT68921, SBI-0206965, MRT67307, MRT68920, MRT68922, MRT199665, LY3009120, dorsomorphine, or any combination thereof. In some embodiments, the VPS inhibitor is PIK-III, VPS34-IN1, SAR405, Spautin-1, NSC185058, or any combination thereof. In some embodiments, the macropinocytosis inhibitor is EIPA (ethyl isopropyl amyloride), wartmannin, amyloride, apyrimod, Dyngo-4a, latruncrin B, or any combination thereof.

[0024] In some embodiments, the Wnt / beta-catenin pathway inhibitor is a beta-catenin inhibitor, a PORCN inhibitor, a GSK3 inhibitor, a CLK inhibitor, or any combination thereof. In some embodiments, the beta-catenin inhibitor is tegavivant, foscenvivant, PRI-724 (also known as ICG-001), C-82, BC2059, or any combination thereof. In some embodiments, the PORCN inhibitor is LGK974 (WNT974), ETC-1922159, CGX1321, CWP232291, or any combination thereof. In some embodiments, the GSK3 inhibitor is tidoglucib, radubiglucib, LiCl (lithium chloride), CHIR99021, SB216763, AZD1080, LY2090314, or any combination thereof. In some embodiments, the CLK inhibitor is SM08502, SM04690, TG003, KH-CB19, T3.5, CX-4945, or any combination thereof. In some embodiments, the JAK / STAT pathway inhibitor is an inhibitor of JAK1, JAK2, JAK3, STAT3, STAT5, or any combination thereof. In some embodiments, the JAK inhibitor is ruxolitinib, fedratinib, tofacitinib, baricitinib, or any combination thereof. In some embodiments, the STAT inhibitor is SD-36, Stattic, S3I-201, OPB-31121, napabucasin (BBI608), or any combination thereof.

[0025] In some embodiments, the epigenetic modifier is an HDAC inhibitor, a BET inhibitor, an EZH2 inhibitor, a Co-REST inhibitor, an EP300 inhibitor, an LSD1 inhibitor, a PRMT5 inhibitor, a MAT2A inhibitor, a DOTL1 inhibitor, or any combination thereof. In some embodiments, the farnesyltransferase inhibitor is tipifarnib, ronafarnib, lilapradib, or any combination thereof. In some embodiments, the TGF beta inhibitor is garnicerutib (LY2157299), bactocerutib (TEW-7197), fresolimmab, reldelimumab, travedersen, curcumin, resveratrol, or any combination thereof. In some embodiments, the HSP90 inhibitor is geldanamycin or its derivatives (e.g., 17-AAG, 17-DMAG), KOS953, radicicol or its derivatives (e.g., PU-H71), SNX-2112, ganetespib, AT13387, onarespib, luminespib, KW-2478, or any combination thereof. In some embodiments, the GPX4 inhibitor is RSL3, ML162, DPI7, FINO2, MCB-613, CBS9106, ML210, ODSH, TLN232, or any combination thereof. In some embodiments, the NRF2 inhibitor is ML385, brusatol, CDDO-Im, RTA-408, trigonelline, or any combination thereof. In some embodiments, the TEAD inhibitor is VT-107, a pan-TEAD inhibitor, VT-104, verteporfin, CA3, a statin, K-975, IAG933, or any combination thereof. In some embodiments, the notch / gamma-secretase inhibitor is nilogacestat. In some embodiments, the hedgehog inhibitor is bismodegib, sonimodegib, glassdegib, or any combination thereof.

[0026] In some embodiments, the chemotherapeutic agent is FOLFOX, FOLFIRI, 5-FU, Tipircil, Trifluridine, TMZ, Docetaxel, Gemcitabine, Abraxane, Paclitaxel, Cisplatin, Carboplatin, Etoposide, or any combination thereof.

[0027] In some embodiments, immunotherapy may be an immune checkpoint inhibitor, cytokine inhibitor, cytokine, vaccine, antibody therapy, bispecific antibody, cell therapy, or any combination thereof. In some embodiments, immunotherapy may be listed in Table 1. In some embodiments, one or more additional therapeutic agents may include an immune checkpoint inhibitor and a chemotherapeutic agent.

[0028] In some embodiments, one or more additional therapeutic agents include a COX1 / 2 inhibitor or a COX1 inhibitor. In some embodiments, one or more additional therapeutic agents include an xCT inhibitor. In some embodiments, the xCT inhibitor is an SLCA11 inhibitor.

[0029] In some embodiments, one or more additional therapeutic agents include PPAR agonists. In some embodiments, one or more additional therapeutic agents include a menin inhibitor. In some embodiments, one or more additional therapeutic agents include PTEN stabilizers.

[0030] In some embodiments, one or more additional therapeutic agents include SGK inhibitors. In some embodiments, one or more additional therapeutic agents include myc inhibitors. In some embodiments, one or more additional therapeutic agents include a DLL3 inhibitor.

[0031] In some embodiments, one or more additional therapeutic agents include a CCR8 inhibitor. In some embodiments, one or more additional therapeutic agents include Sting agonists. In some embodiments, one or more additional therapeutic agents include an SCD1 inhibitor.

[0032] In some embodiments, one or more additional therapeutic agents include a GSPT1 inhibitor. In some embodiments, the inhibitor is MRT-2359. In some embodiments, one or more additional therapeutic agents include NEK7 modifiers.

[0033] In some embodiments, one or more additional therapeutic agents include hormone receptor modulators. In some embodiments, one or more additional therapeutic agents include a CTLA-4 inhibitor. In some embodiments, the CTLA-4 inhibitor is botensilimab. In some embodiments, the combination further includes an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is valstilimab.

[0034] In some embodiments, the combination includes an EGFR inhibitor and pembrolizumab. In some embodiments, the combination includes an SHP2 inhibitor, an immune checkpoint inhibitor, and a CTLA-4 inhibitor.

[0035] In some embodiments, the combination further comprises one or more pharmaceutically acceptable excipients. In some embodiments, the RAS(ON) inhibitor(s) and one or more additional therapeutic agents are administered simultaneously.

[0036] In some embodiments, the RAS(ON) inhibitor(s) and one or more additional therapeutic agents are administered sequentially. In some embodiments, the RAS(ON) inhibitor(s) and one or more additional therapeutic agents are formulated in a single composition.

[0037] In some embodiments, the RAS(ON) inhibitor(s) and one or more additional therapeutic agents are formulated in separate compositions. Any limitations discussed in relation to one embodiment of this disclosure are specifically intended to be applicable to any other embodiment of this disclosure. Furthermore, any compound or composition of this disclosure may be used in any manner of this disclosure, and any compound or composition of this disclosure may be produced or utilized by any manner of this disclosure. [Brief explanation of the drawing]

[0038] [Figure 1] In a KRASG12C NSCLC xenograft model, the RMC-6291 + RMC-6236 combination doublet overcomes resistance and extends durability. In the graph titled "Improved Response," the conditions tested, from left to right, are RMC-6291 100 or 200 mg / kg po qd, RMC-6236 25 mg / kg po qd, and the combination. [Figure 2] In a KRASG12C NSCLC xenograft model, combination therapy with RMC-6291 + RMC-6236 induces apoptosis, drives sustained tumor regression, and prevents resistance. [Figure 3] This demonstrates that RMC-6291 + RMC-6236 provide a combined benefit in the KRASG12C PDX model. [Figure 4] The benefits of the RMC-6236 + chemotherapy combination in the PDAC KRASAMP model are illustrated. [Figure 5] The RAS inhibition by RMC-7977 completely suppresses PI3K-active KRASWT and KRASG12D, exhibits moderate inhibitory effects in KRASG12C and KRASG12V, and has no effect in KRASG12R strains (left). RMC-7977 suppresses PIP3 levels only in KRASG12D mutant PDAC strains, but not in KRASG12R mutant PDAC strains (right). [Figure 6]The image shows that RMC-7977 reduced pERK (MAPK signaling) levels in both KRASG12D and KRASG12R mutant cell lines (left), while the MEK inhibitor reduced pERK (MAPK signaling) levels in both KRASG12D and KRASG12R mutant cell lines (right). [Figure 7] We demonstrate that the combination of RMC-9805 and abemaciclib drives a durable and complete response in an immunoassay-qualified model of PDAC. [Modes for carrying out the invention]

[0039] This disclosure relates, in general, to compositions and methods, including combination therapies for treating RAS-related diseases or disorders. In certain embodiments, this disclosure provides combination therapies for treating cancers having RAS mutations. In each embodiment, the compositions and methods include a RAS(ON) inhibitor therapy (e.g., RMC-6236, RMC-6291, or RMC-9805). In some embodiments, this disclosure provides compositions and methods comprising a RAS(ON) inhibitor therapy and one or more additional therapeutic agents. In certain embodiments, the combination therapies of this disclosure synergistically increase the potency of the activators disclosed herein. In certain embodiments, the combination therapies of this disclosure provide patients with improved clinical benefits compared to treatment with the activators disclosed herein as monotherapy (e.g., increased progression-free survival).

[0040] Overall method In the practice of this disclosure, unless otherwise indicated, the prior arts of cell culture, molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology are used, and these are within the scope of the art. Such techniques are described in Molecular Cloning: A Laboratory Manual, third edition (Sambrook et al., 2001) Cold Spring Harbor Press; Oligonucleotide Synthesis (P. Herdewijn, ed., 2004); Animal Cell Culture (RIFreshney), ed., 1987); Immunology (DMWeir & C.C. Blackwell, eds.), Gene Transfer Vectors for Mammalian Cells (JMMiller & M.P. Calos, eds., 1987), Current Protocols in Molecular Biology (FMAusubel et al., eds., 1987), PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994), Current Protocols in Immunology(JEColigan et al., eds., 1991), Short Protocols in Molecular Biology (Wiley and Sons, 1999), Manual of Clinical Laboratory Immunology (B. Detrick, NRRose, and JDFolds eds., 2006), Immunochemical Protocols (J. Pound, ed., 2003), Lab Manual in Biochemistry: Immunology and Biotechnology (A. Nigam and A. Ayyagari, eds.This is fully explained in the following literature (2007), *Immunology Methods Manual: The Comprehensive Sourcebook of Techniques* (Ivan Lefkovits, ed., 1996), *Using Antibodies: A Laboratory Manual* (E. Harlow and D. Lane, eds., 1988), and others.

[0041] definition In this application, unless otherwise clearly indicated by context, (i) the terms “a” and “an” mean “one or more”; (ii) the term “or” is used to mean “and / or” unless it is explicitly intended to refer only to the options or the options are not mutually exclusive, but this disclosure supports definitions referring only to the options and “and / or”; (iii) the terms “comprising” and “including” are understood to encompass the itemized components or steps, whether presented by themselves or together with one or more additional components or steps; and (iv) where a scope is indicated, it includes endpoints.

[0042] As used herein, the term “approximately” is used to indicate that a value includes the standard deviation of the error of the device or method used to determine the value. In certain embodiments, unless otherwise stated or evident from the content (for example, if such a number exceeds 100% of the possible values), the term “approximately” refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1% or less in either direction (above or below) of the stated value.

[0043] Throughout this specification, unless the context requires otherwise, the terms “comprise,” “comprises,” and “comprising” mean to include the steps or elements, or groups of steps or elements, described, but not to exclude any other steps or elements, or groups of steps or elements. “Consisting of” means to include, and is limited to, everything that follows the phrase “consisting of.” Thus, the phrase “consisting of” indicates that the listed elements are necessary or essential, and other elements may or may not be present. “Essentially consisting of” means to include any elements listed after this phrase, and, with respect to other elements, is limited to those that do not interfere with or contribute to the activity or effect specified in the disclosure of the listed elements. Thus, the phrase “essentially consisting of” indicates that the listed elements are necessary or essential, but other elements are optional, and may or may not be present, depending on whether they substantially affect the activity or effect of the listed elements.

[0044] Those skilled in the art will understand that certain inhibitor compounds described herein may exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., one or more atoms are substituted with different isotopes, such as deuterium-substituted hydrogen). Unless otherwise indicated or made clear from the context, the described structures can be understood to represent any such isomeric or isotopic forms, individually or in combination.

[0045] The inhibitor compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds containing asymmetrically substituted carbon atoms may be isolated in an optically active form or as a racemate. Methods for preparing optically active forms from optically active starting materials, such as by the division of racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers, such as olefins and C=N double bonds, may also exist among the compounds described herein, and all such stable isomers are intended in this disclosure. Cis and trans geometric isomers of the compounds in this disclosure are described and may be isolated as mixtures of isomers or as separated isomers.

[0046] In some embodiments, one or more inhibitor compounds described herein may exist in different tautomerized forms. As will be apparent from the context, unless explicitly excluded, references to such compounds encompass all such tautomerized forms. In some embodiments, the tautomerized form arises from the exchange of a single bond with an adjacent double bond and the accompanying transfer of protons. In certain embodiments, the tautomerized form may be a prototropic tautomer, which is a protonated state of an isomer having the same empirical formula and total charge as the reference form. Examples of moieties having prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, amide-imoid acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. In some embodiments, the tautomers can be in equilibrium or sterically fixed to one form by appropriate substitution. In certain embodiments, the tautomers arise from acetal interconversion.

[0047] Unless otherwise indicated, inhibitor compounds described herein also mean compounds that differ only in that one or more isotopically enriched atoms are present. Exemplary isotopes that can be incorporated into the compounds of the present disclosure include 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I and the like, and isotopes such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine. Isotopically labeled compounds (e.g., 3 H and 14 C labeled compounds) may be useful in compound or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful in terms of the ease of their preparation and detectability. Further, substitution with heavier isotopes, such as deuterium (i.e., 2 H), can result in higher metabolic stability and, as a result, certain therapeutic advantages can be obtained (e.g., longer in vivo half-life or lower required dosage). In some embodiments, one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C or 14 C enriched carbon. 15 O, 13 N, 11 C, and 18Positron-emitting isotopes such as fluorine are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by replacing unlabeled reagents with isotopically labeled reagents, following procedures similar to those disclosed for the compounds of this disclosure described herein.

[0048] As is known in the art, many chemical components can be used in various different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the inhibitor compound may be used in any such form, including any solid form. In some embodiments, the compound may be provided or used in hydrate or solvate form.

[0049] Those skilled in the art reading this disclosure will understand that inhibitor compounds may be provided or utilized in any of a variety of forms, such as salt form, protected form, prodrug form, ester form, isomer form (e.g., optical or structural isomer), isotopic form, etc. In some embodiments, reference to a particular compound may relate to a particular form of that compound. In some embodiments, reference to a particular compound may relate to that compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound from a racemic mixture of the compound; a particular salt of a compound may be considered a different form from another salt form of the compound; a preparation containing one structural isomer of a double bond ((Z) or (E)) may be considered a different form from one containing the other structural isomer of the double bond ((E) or (Z)); and a preparation in which one or more atoms are isotopes different from those present in the reference preparation may be considered a different form.

[0050] As used herein, the term “administration” means the administration of a composition (e.g., a compound, or a preparation containing a compound as described herein) to a subject or system. Administration also includes administering to a subject a prodrug derivative or analog of a compound, or a pharmaceutically acceptable salt of a compound or composition, which can form an equivalent amount of the active compound in the subject’s body. Administration to an animal subject (e.g., a human) may be by any suitable route. For example, in some embodiments, administration may be bronchial (including bronchial infusion), cheek, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, transnasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, intratracheal (including intratracheal infusion), transdermal, vaginal, or intravitreous.

[0051] As used herein, the term “amino acid” refers to a molecule having a side chain, an amino group, and an acidic group (e.g., -CO2H or -SO3H), and an amino acid is bonded to a parent molecule by a side chain, an amino group, or an acidic group (e.g., a side chain). As used herein, the term “amino acid” in its broadest sense refers to any compound or substance that can be incorporated into a polypeptide chain, for example, by the formation of one or more peptide bonds. In some embodiments, the amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a synthetic amino acid, in some embodiments, the amino acid is a D-amino acid, and in some embodiments, the amino acid is an L-amino acid. “Standard amino acid” refers to any of the 20 standard L-amino acids commonly found in naturally occurring peptides. Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolicine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0052] As used herein, “amino acid substitution” refers to the substitution of a wild-type amino acid in a protein with a non-wild-type amino acid. Amino acid substitutions can be caused by gene mutations and can alter one or more properties of a protein (for example, altered binding affinity or specificity, altered enzyme activity, altered structure, or altered function).

[0053] The term "combination therapy" refers to a treatment method that includes administering to a subject, as part of a treatment regimen, at least two therapeutic agents, optionally as one or more pharmaceutical compositions. For example, combination therapy may include the administration of a single pharmaceutical composition comprising at least two therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. Combination therapy may include the administration of two or more pharmaceutical compositions, each comprising one or more therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. The two or more agents may optionally be administered simultaneously (as a single or separate composition) or sequentially (as separate compositions). The therapeutic agents may be administered in an effective dose. The therapeutic agents may be administered in a therapeutically effective dose. In some embodiments, the effective dose of one or more therapeutic agents may be less when used in combination therapy than the therapeutic dose of the same therapeutic agent when used as a monotherapy, for example, due to the added or synergistic effect of combining two or more therapeutic agents.

[0054] As used herein, “effective dose,” “therapeutically effective” combination, or “therapeutically effective” dose refers to an amount sufficient to induce a desired biological response. In this disclosure, the desired biological response is to treat a patient’s (i.e., subject requiring treatment with combination therapy) disease or disorder (e.g., cancer), such as slowing the progression of the disease or disorder or reducing the presence of the disease or disorder in the patient. In this disclosure, “patient” is understood to refer to a patient requiring treatment with a combination of therapeutic agents (e.g., a RAS(ON) inhibitor and an additional therapeutic agent). The exact amounts of the first and second therapeutic agents administered to a patient depend on the mode of administration, the type and severity of the disease or disorder, and the subject’s characteristics such as general health, age, sex, weight, and drug tolerance. In some embodiments, the effective doses of the first and second therapeutic agents in combination are different from the effective doses of the first and / or second therapeutic agents administered as monotherapy. In some embodiments, the effective doses of the first and second therapeutic agents in a combination are the same as the effective doses of the first and / or second therapeutic agents administered as monotherapies. In some embodiments, a therapeutically effective combination of the first and second therapeutic agents refers to amounts of the first and second therapeutic agents that are different from the therapeutically effective doses of the first and second therapeutic agents administered as monotherapies. In some embodiments, a therapeutically effective combination of the first and second therapeutic agents refers to amounts of the first and second therapeutic agents that are the same as the therapeutically effective dose of one of the first and second therapeutic agents administered as monotherapies.

[0055] The term “therapeutic dose” means an amount sufficient to treat a disease, disorder, or condition when administered to a population suffering from or suspected of having a disease, disorder, or condition, according to a therapeutic administration regimen. In some embodiments, the therapeutic dose is an amount that reduces the onset or severity of one or more symptoms of the disease, disorder, or condition, or delays the onset of one or more symptoms of the disease, disorder, or condition. Those skilled in the art will understand that the term “therapeutic dose” does not actually require that successful treatment be achieved in a particular individual. Rather, the therapeutic dose can be an amount that, when administered to subjects requiring such treatment, produces a particular desired pharmacological response in a significant number of subjects. It is specifically understood that a particular subject may actually be “refractory” to the “therapeutic dose.” In some embodiments, the reference to the therapeutic dose may refer to an amount measured in one or more specific tissues (e.g., tissues affected by the disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, the therapeutically effective dose may be formulated or administered as a single dose. In some embodiments, the therapeutically effective dose may be formulated or administered in multiple doses, for example, as part of an administration regimen.

[0056] As used herein, the term “dosage form” refers to a physically distinct unit of a compound (e.g., an inhibitor compound disclosed herein) for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, such an amount is a unit dose (or its entire fraction) appropriate for administration according to an administration regimen (i.e., using a therapeutic administration regimen) that has been determined to correlate with a desired or beneficial outcome when administered to a suitable population. Those skilled in the art will understand that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve administration in multiple dosage forms.

[0057] As used herein, the term “dosage regimen” refers to a set of unit doses (usually two or more) administered individually to a subject, typically separated by time periods. In some embodiments, a given therapeutic compound has a recommended dosage regimen, which may involve one or more doses. In some embodiments, a dosage regimen comprises multiple doses, each separated from the others by time periods of the same length, and in some embodiments, a dosage regimen comprises multiple doses and at least two different time periods separating the individual doses. In some embodiments, all doses within a dosage regimen are the same unit dose. In some embodiments, different doses within a dosage regimen are different amounts. In some embodiments, a dosage regimen comprises a first dose at a first dose, followed by one or more further doses at a second dose different from the first dose. In some embodiments, a dosage regimen comprises a first dose at a first dose, followed by one or more further doses at a second dose the same as the first dose. In some embodiments, the administration regimen correlates with desired or beneficial outcomes when administered across the relevant population (i.e., it is a therapeutic administration regimen). When administered in combination with RAS(ON) inhibitors, the dosage of one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may be reduced from the standard monotherapy dosage. In certain embodiments, the dosage may be determined empirically from the combination and order of drugs, or estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).

[0058] The term “disability” is used in this disclosure to mean, and is interchangeable with, the terms “disease,” “condition,” or “illness,” unless otherwise indicated. As used herein, the term “isomer” means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the Disclosure. The compounds of the Disclosure may have one or more chiral centers or double bonds and are therefore recognized to exist as stereoisomers, e.g., double bond isomers (i.e., geometric E / Z isomers), or diastereomers (i.e., enantiomers (i.e., (+) or (-)), or cis / trans isomers). According to the Disclosure, the chemical structures illustrated herein encompass both all corresponding stereoisomers, i.e., stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereoisomerically pure forms) and mixtures of enantiomers and stereoisomers, e.g., racemic compounds. Mixtures of enantiomers and stereoisomers of the compounds disclosed herein can typically be separated into their constituent enantiomers or stereoisomers by known methods, such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts by known asymmetric synthesis methods.

[0059] As used herein, the term “inhibitor” refers to a compound that prevents a biomolecule (e.g., protein, nucleic acid) from completing or initiating a reaction. Inhibitors can inhibit a reaction by competitive, non-competitive, or non-competitive means, for example. With respect to its binding mechanism, an inhibitor may be an irreversible or reversible inhibitor. Exemplary inhibitors include, but are not limited to, nucleic acids, DNA, RNA, shRNA, siRNA, proteins, protein mimics, peptides, peptide mimics, antibodies, small molecules, degradation agents, chemicals, enzymes, receptors, or analogs that mimic the binding sites of other proteins. In some embodiments, the inhibitor is a small molecule, for example, a low molecular weight organic compound, for example, an organic compound having a molecular weight (MW) of less than 1200 Daltons (Da). In some embodiments, the MW is less than 1100 Da. In some embodiments, the MW is less than 1000 Da. In some embodiments, the MW is less than 900 Da. In some embodiments, the MW is less than 800 Da. In some embodiments, the MW is less than 700 Da. In some embodiments, the MW is less than 600 Da. In some embodiments, the MW range of the small molecule is 600 Da to 700 Da (inclusive). In some embodiments, the MW range of the small molecule is 600 Da to 800 Da (inclusive). Small molecule inhibitors include cyclic and acyclic compounds. Small molecule inhibitors include their native products, derivatives, and analogs. Small molecule inhibitors may include covalent crosslinking groups capable of forming covalent crosslinks with, for example, the amino acid side chains of a target protein.

[0060] In some embodiments, inhibitors are molecular entities designed to selectively induce the degradation of target proteins within cells, such as proteolytic agents, or proteolytic targeting chimeras (PROTACs). Proteolytic agents such as PROTACs typically consist of bifunctional molecules that simultaneously bind to both the target protein of interest and components of the cellular degradation mechanism, such as E3 ubiquitin ligases. This dual binding promotes the ubiquitination of the target protein, leading to its recognition by the proteasome and subsequent degradation. The design and optimization of proteolytic agents may include structural modifications, linker optimization, and functional characterization to enhance their specificity, potency, and selectivity for the target protein.

[0061] As used herein, the term “mutation” refers to any modification of a nucleic acid or polypeptide that results in an alteration of the nucleic acid or polypeptide. The term “mutation” may include, for example, point mutations, deletions or insertions of one or more residues within a polynucleotide, alterations occurring within the protein-coding region of a gene, and alterations in regions outside the protein-coding region, such as, but not limited to, regulatory or promoter sequences, and amplification, or chromosomal disruption or translocation. In certain embodiments, a mutation results in an amino acid substitution in the encoded protein.

[0062] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cattle, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus macaque.

[0063] The terms “prevent” or “prevention” in relation to a subject refer to preventing the subject from contracting a disease or disorder. Prevention includes prophylactic treatment. For example, prevention may include administering a compound disclosed herein to a subject before the subject contracts a disease, and this administration prevents the subject from contracting the disease.

[0064] As used herein, the term “pharmaceutical composition” means a compound such as the compounds of this disclosure, or a pharmaceutically acceptable salt thereof, formulated with pharmaceutically acceptable excipients.

[0065] As used herein, “pharmaceutically acceptable excipients” refers to any inert component (e.g., a vehicle capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in the subject matter. Typical excipients include, for example, antifouling agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavoring agents, fragrances, flow enhancers, lubricants, preservatives, printing inks, adsorbents, suspending agents or dispersants, sweeteners, or hydration water. Examples of excipients include, but are not limited to, optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolic acid, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are familiar with a wide variety of agents and materials useful as excipients.See, for example, Ansel, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0066] As used herein, the term “pharmaceutically acceptable salt” refers to salts of the compounds described herein that are suitable for use in contact with human and other animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., within the normal range of reasonable medical judgment, and that are balanced by a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PHStahl and CGWermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting free base groups with suitable organic acids.

[0067] The terms "RAS inhibitor" and "inhibitor of RAS" are used interchangeably and refer to any inhibitor that targets the RAS protein, i.e., selectively binds to or selectively inhibits the RAS protein.

[0068] As used herein, the term “RAS(OFF) inhibitor” refers to an inhibitor that targets, i.e., selectively binds to or selectively inhibits the GDP-bound inactive state of RAS (e.g., more selectively than GTP-bound active RAS). Inhibition of the GDP-bound inactive state of RAS can be achieved, for example, by inhibiting the exchange of GDP with GTP, thereby sequestering the inactive state and inhibiting the adaptation of RAS to its active conformation. In certain embodiments, RAS(OFF) inhibitors may also bind to or inhibit the GTP-bound active state of RAS (e.g., with lower affinity or inhibition constant than GDP-bound inactive RAS). RAS(OFF) inhibitors may be mutaselective, such as being selective for G12C, G12D, or G12V variants. RAS(OFF) inhibitors may be selective for more than one variant, or selective for one or more variants and the wild type (in either case, “pan-KRAS(OFF)” inhibitors). Methods for measuring RAS(OFF) inhibition are known in the art.

[0069] As used herein, "RAS(ON) multiselective inhibitor" and "RAS MULTI "Inhibitor", "RAS MULTI The terms “(ON) inhibitor” or “RAS(MULTI) inhibitor” refer to RAS inhibitors of at least three RAS isoforms, including 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. In a non-limiting example, RMC-6236 and RMC-7977 are RAS(ON) multiselective inhibitors.

[0070] As used herein, the term “RAS(ON) variant-selective inhibitor” refers to a RAS inhibitor of a single variant carrying a missense mutation. In a non-limiting example, RMC-6291 is a RAS inhibitor.G12C It is a RAS(ON) variant-selective inhibitor (also referred to as a "RAS(ON)G12C selective inhibitor"). In another non-specific example, RMC-9805 is a RAS G12D It is a RAS(ON) variant-selective inhibitor (also known as a "RAS(ON)G12D selective inhibitor").

[0071] The terms “RAS pathway” and “RAS / MAPK pathway” are used interchangeably herein and refer to a signal transduction cascade downstream of various cell surface growth factor receptors, where the activation of RAS (and its diverse isoforms and allotypes) is a central event driving various cellular effector events that determine cell proliferation, activation, differentiation, mobility, and other functional properties. SHP2 transmits a positive signal from the growth factor receptor to the RAS activation / deactivation cycle, which is regulated by guanine nucleotide exchange factors (GEFs such as SOS1) that load GTP into RAS to produce functionally active, GTP-bound RAS, and GTP-accelerating proteins (GAPs such as NF1) that facilitate the termination of the signal by converting GTP to GDP. The GTP-bound RAS produced by this cycle transmits essential positive signals to a series of serine / threonine kinases, including RAFs and MAP kinases, from which further signals spread in various ways.

[0072] A “therapeutic agent” is any substance, such as a compound or composition, that is capable of treating a disease or disorder. In some embodiments, therapeutic agents useful in combination with the present disclosure include RAS inhibitors and cancer chemotherapy agents. Many such therapeutic agents are known in the art and are disclosed herein.

[0073] The term “treatment” (and in addition, “to treat” or “to treat”) in its broadest sense refers to any administration of a substance (e.g., a compound of the Disclosure) that partially or completely alleviates, improves, reduces, inhibits, delays the onset, reduces the severity, or decreases the incidence of one or more symptoms, features, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment may be administered to a subject that shows no signs of the related disease, disorder, or condition, or to a subject that shows only the initial signs of the disease, disorder, or condition. Alternatively, or in addition, in some embodiments, treatment may be administered to a subject that shows one or more established signs of the related disease, disorder, or condition. In some embodiments, treatment may be administered to a subject that has been diagnosed with the related disease, disorder, or condition. In some embodiments, treatment may be administered to a subject that is known to have one or more susceptibility factors that are statistically correlated with an increased risk of progression of the related disease, disorder, or condition. In any treatment method of the Spec, a patient or subject may require such treatment.

[0074] The term "tricomplex" refers to a mechanism of action involving the formation of a high-affinity tricomplex between a synthetic ligand (e.g., a RAS(ON) inhibitor) and two intracellular proteins that do not normally interact under physiological conditions: RAS, the target protein of interest, and cyclophyllin A, a cytosolic chaperone protein widely expressed in cells. Such tricomplexes are known in the art. See, for example, WO2020 / 132597, WO2021 / 091956, WO2021 / 091967, WO2021 / 091982, WO2022 / 060836, WO2022 / 235864, WO2022 / 235870, WO2023 / 060253, WO2023 / 133543, and WO2023 / 240263.

[0075] The term "wild-type" refers to an entity with a structure or activity that is found in a "normal" state or context in nature (as opposed to mutants, diseases, modified organisms, etc.). Those skilled in the art will understand that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0076] I. Combination Therapy Compositions comprising an RAS(ON) inhibitor and one or more therapeutic agents for use in the treatment of RAS-related diseases or disorders are provided herein. In certain embodiments, the composition of the Disclosure comprises two or more RAS(ON) inhibitor therapies. In certain embodiments, the composition of the Disclosure comprises an RAS(ON) inhibitor therapy and one additional therapeutic agent. In certain embodiments, the composition of the Disclosure comprises an RAS(ON) inhibitor therapy and two additional therapeutic agents. In certain embodiments, the composition of the Disclosure comprises an RAS(ON) inhibitor therapy and three additional therapeutic agents. In certain embodiments, the composition of the Disclosure comprises an RAS(ON) inhibitor therapy and four or more additional therapeutic agents.

[0077] Pharmaceutical compositions comprising combinations thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients are also provided. Compositions comprising combinations of therapeutic agents may be used, as described herein, in methods for modulating the RAS (e.g., in subjects or cells) and in methods for treating RAS-related diseases and disorders. This disclosure provides, among other things, compositions, methods, and kits for treating or preventing RAS-related diseases or disorders (e.g., cancer).

[0078] The RAS(ON) inhibitors disclosed herein may be administered before, after, or concurrently with one or more such additional therapies. When combined, the dosage of the RAS(ON) inhibitor and the dosage of one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may provide a therapeutic effect (e.g., a synergistic or additive therapeutic effect). The RAS(ON) inhibitors and additional therapies, such as anticancer agents, disclosed herein may be administered together, such as in a single pharmaceutical composition, or separately. If administered separately, they may be administered simultaneously or sequentially. Such sequential administrations may have close or long intervals between doses.

[0079] All references herein, whether expressly stated or not, are incorporated herein by reference to the drugs described herein, including the compounds or molecular structures disclosed herein.

[0080] a) RAS(ON) inhibitors The compositions and methods of this disclosure include RAS(ON) inhibitors. In certain embodiments, RAS(ON) inhibitors useful to this disclosure may form a high-affinity triplicate or conjugate between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: a target protein of interest (e.g., RAS) and a cytosolic chaperone (presenter protein) that is widely expressed intracellularly (e.g., cyclophyllin A). More specifically, in some embodiments, the RAS inhibitors described herein induce a novel binding pocket in RAS by driving the formation of a high-affinity triplicate or conjugate between the RAS protein and the widely expressed cytosolic chaperone cyclophyllin A (CYPA). In some embodiments, the RAS(ON) inhibitor is a RAS(ON) multiselective inhibitor (e.g., RMC-6236, RMC-7977, or GFH547). In some embodiments, the RAS(ON) inhibitor is a mutation-selective inhibitor (e.g., RMC-6291 or RMC-9805).

[0081] In some embodiments, the RAS(ON) inhibitor is an inhibitor that selectively binds to and inhibits the active state of RAS bound to GTP. In certain embodiments, the RAS(ON) inhibitor may also bind to or inhibit the inactive state of RAS bound to GDP (for example, with lower affinity or inhibition constant than the active state of RAS bound to GTP). In some embodiments, the RAS(ON) inhibitor has a molecular weight of 800 to 1200 Da (including both ends). References to the term RAS(ON) inhibitors can be found in WO2021 / 091956, WO2021 / 091982, WO2021 / 091967, WO2022 / 060836, WO2022 / 235864, WO2022 / 235870, WO2022 / 251292, WO2023 / 133543, WO2023 / 015559, WO20 23 / 025832, WO2023 / 060253, WO2023 / 133543, WO2023 / 240263, or PCT application serial numbers PCT / US2023 / 037057, PCT / US2024 / 023272, PCT / US2024 / 023208, or WO2024 / 067857, WO2024 This includes, but is not limited to, any one or more RAS(ON) inhibitors selected from those disclosed in / 060966, WO2024 / 017859, WO2024 / 008834, WO2024 / 008610, WO2023 / 232776, WO2023 / 208005, WO2023 / 086341, WO2023 / 025832, WO2023 / 015559, CN117720556, CN117720555, CN117720554, CN1177534687, CN11753685, or CN11753684 (each of which is invoked by reference in whole or in combination of such RAS(ON) inhibitors). Methods for determining RAS(ON) inhibition are known in the art. See, for example, WO2021 / 091956 and WO2022 / 060836.

[0082] In some embodiments, the RAS(ON) inhibitor is compound A647 of WO2021 / 091982. In some embodiments, the RAS(ON) inhibitor is compound A122 of WO2022 / 060836. In some embodiments, the RAS inhibitor therapy comprises two or more RAS(ON) inhibitors.

[0083] In some embodiments, the RAS(ON) inhibitor is RMC-6236.

[0084] [ka]

[0085] In some embodiments, the RAS(ON) inhibitor is RMC-7977.

[0086] [ka]

[0087] In some embodiments, the RAS(ON) inhibitor is RMC-6291.

[0088] [ka]

[0089] In some embodiments, the RAS(ON) inhibitor is RMC-4998.

[0090] [ka]

[0091] In some embodiments, the RAS(ON) inhibitor is RMC-9805.

[0092] [ka]

[0093] In non-limiting examples, RAS(ON) inhibitor therapy includes RMC-6236 and RMC-6291 or RMC-6236 and RMC-9805. The synthesis of RAS(ON) inhibitors is known by known synthetic methods in the field of synthetic organic chemistry, or with variations thereof as understood by those skilled in the art, as described, for example, in WO2021 / 091956, WO2021 / 091982, or WO2022 / 060836.

[0094] b) RAS / MAPK inhibitors The compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more RAS / MAPK pathway inhibitors. The RAS / MAPK pathway refers to a signal transduction cascade downstream of various cell surface growth factor receptors, where activation of RAS (and its diverse isoforms and allotypes) is a central event driving a variety of cellular effector events that determine cell proliferation, activation, differentiation, mobility, and other functional properties. SHP2 transmits a positive signal from the growth factor receptor to the RAS activation / deactivation cycle, which is regulated by guanine nucleotide exchange factors (GEFs such as SOS1) that load GTP into RAS to produce functionally active, GTP-bound RAS, and GTP-accelerating proteins (GAPs such as NF1) that facilitate the termination of the signal by converting GTP to GDP. The GTP-bound RAS produced by this cycle transmits essential positive signals to a series of serine / threonine kinases, including RAF and MAP kinase, from which further signals extend to various cellular effector functions. In some embodiments, therapeutic agents that can be combined with RAS(ON) inhibitors are inhibitors of the MAP kinase (MAPK) pathway (or "MAPK inhibitors"). MAPK pathway inhibitors include, but are not limited to, one or more MAPK pathway inhibitors described in Cancers (Basel) 2015 Sep;7(3):1758-1784.For example, MAPK inhibitors include trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS5132, vemurafenib, pimacertib, TAK733, RO4987655 (CH4987655), CI-1040, PD-0325901, CH5126766, MAP855, AZD6244, refametinib (RDEA119 / BAY86-9766), GDC-0973 / XL581, AZD8330 (ARRY-424704 / ARRY-704), RO5126766 (Roche, PLoS One. 2014 Nov). One or more of the following may be selected (as described in 25;9(11)) and GSK1120212 (or JTP-74057, as described in Clin Cancer Res. 2011 Mar 1;17(5):989-1000). MAPK pathway inhibitors may be PLX8394, LXH254, GDC-5573, or LY3009120. MAPK pathway inhibitors may be PI3Kα:RAS disruptors such as BBO-10203.

[0095] i) RAS(OFF) inhibitors and RAS(OFF) degrading agents The compositions and methods described herein may include RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more RAS(OFF) inhibitors. Numerous mutant-selective and pan-KRAS inhibitors have been disclosed. 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 inactive RAS protein and blocking its activation and downstream signaling.

[0096] In some embodiments, the RAS(OFF) inhibitor is a KRAS(OFF) inhibitor having a molecular weight of less than 700 Da. The term "KRAS(OFF) inhibitor" refers to any RAS(OFF) inhibitor that binds to KRAS at its GDP-bound "off" position. In some embodiments, the KRAS(OFF) inhibitor is a KRAS G12CIt is specific to the mutation. KRAS G12C (OFF) inhibitors are KRAS G12C Using covalent groups that allow for selective targeting of mutant proteins, many such inhibitors contain a pyrimidine core. (KRAS) G12C (OFF) All inhibitors are KRAS G12C KRAS targets identical cysteine ​​residues within mutant proteins, inducing a structural change that fixes the protein in an inactive state. G12C (OFF) inhibitors include AMG510 (sotrasib), MRTX849 (adagrasib), MRTX1257, GDC-6036 (divalasib), JDQ443 (opnurasib), ERAS-3490, LY3537982 (olomorasib), BI1823911, BPI-421286, JAB-3312, JAB-21000, JAB- This includes, but is not limited to, 21822 (glecilassib), D-1553, D3S-001, HBI-2438, HS-10370, MK-1084, YL-15293, BBO-8520 (ON / OFF inhibitor), FMC-376 (ON / OFF inhibitor), GEC255, BBO-11818, and GFH925 (IBI351). In some embodiments, the KRAS(OFF) inhibitor is selected from AMG510 and MRTX849. In some embodiments, the KRAS(OFF) inhibitor is AMG510. In some embodiments, the KRAS(OFF) inhibitor is selected from BPI-421286, JNJ-74699157 (ARS-3248), LY3537982, MRTX1257, ARS853, ARS1620, or GDC-6036.

[0097] In some embodiments, the KRAS(OFF) inhibitor is KRAS G12D It is specific to the mutation. Many KRAS G12D (OFF) inhibitors start with RAS G12C It was developed using (OFF) inhibitors and therefore shares a G12C inhibitor skeleton when combined with other chemical components such as piperazine compounds. KRAS G12DNon-exclusive examples of (OFF) inhibitors include MRTX1133, MRTX282, JAB-22000, ERAS-4, ERAS-5024, HRS-4642, BI-2852, BI-2852, ASP3082, TH-Z827, TH-Z835, QTX-3046, GFH375 (VS-7375), INCB161734, and KD-8.

[0098] In some embodiments, the small molecule RAS(OFF) inhibitor is KRAS G12V It is specific to the mutation. In some embodiments, the small molecule RAS(OFF) inhibitor is KRAS G13DThey are specific to the mutation. In some embodiments, the small molecule RAS(OFF) inhibitor is a pan-KRAS(OFF) inhibitor. In some embodiments, references to the term RAS(OFF) inhibitor include any such RAS(OFF) inhibitor disclosed in any one of the following patent applications: WO2024085661, WO2024083258, WO2024083256, WO2024083246, WO2024083168, WO2024078555, WO2024076674, WO2024076672, WO2024076670, WO2024067714, WO2024067575, WO202406433 5, WO2024063578, WO2024063576, WO2024061370, WO2024061333, WO2024061267, WO2024056063, WO2024055112, WO2024054926, WO202405464 7, WO2024054625, WO2024051763, WO2024051721, WO2024050742, WO2024050640, WO2024046406, WO2024046370, WO2024045066, WO2024044667 , WO2024044649, WO2024044334, WO2024041621, WO2024041606, WO2024041589, WO2024041573, WO2024040131, WO2024040109, WO2024040080 , WO2024036270, WO2024034657, WO2024034593, WO2024034591, WO2024034123, WO2024032747, WO2024032704, WO2024032703, WO2024032702 , WO2024031088, WO2024030647, WO2024030633, WO2024029613, WO2024022507, WO2024022444, WO2024020159, WO2024019103, WO2024017859 , WO2024017392, WO2024015731, WO2024015262, WO2024012456, WO2024009191, WO2024008179, WO2024008178, WO2024008068, WO2024006445,WO2024006424, WO2024002373, WO2023287896, WO2023287730, WO2023284881, WO2023284730, WO2023284537, WO2023283933, WO2023283213, WO202328 0280, WO2023280136, WO2023280026, WO2023278600, WO2023274383, WO2023327324, WO2023246914, WO2023246903, WO2023246777, WO2023244713, WO2 023244615, WO2023244604, WO2023244600, WO2023244599, WO2023230190, WO2023226630, WO2023225302, WO2023225252, WO2023220421, WO202321994 1, WO2023217148, WO2023215802, WO2023215801, WO2023213269, WO2023212548, WO2023208005, WO2023205719, WO2023199180, WO2023198191, WO2023 197984、WO2023190748、WO2023185864、WO2023183755、WO2023183585、WO2 023179703、WO2023179629、WO2023173017、WO2023173016、WO2023173014、W O2023172737, WO2023171781, WO2023159087, WO2023159086, WO2023154766, WO2023152255, WO2023151674, WO2023151621, WO2023150394, WO2023150 284, WO2023143623, WO2023143605, WO2023143352, WO2023143352, WO2023143312, WO2023141570, WO2023141300, WO2023138662, WO2023138601, WO20 23138589, WO2023138524, WO2023133183, WO2023133181, WO2023130012, WO2023125989, WO2023125627, WO2023122662, WO2023122154, WO2023120742WO2023119677, WO2023117681, WO2023116934, WO2023116895, WO2023114733, WO2023105491, WO2023104018, WO2023103906, WO2023103523, WO202310 1928, WO2023099624, WO2023099624, WO2023099620, WO2023099612, WO2023099608, WO2023099592, WO2023098832, WO2023098425, WO2023097227, WO2 023081840, WO2023081476, WO2023078424, WO2023077441, WO2023072297, WO2023072188, WO2023066371, WO2023064857, WO2023061463, WO202306129 4、WO2023057985、WO2023056951、WO2023056421、WO2023051586、WO2023049697、WO2023046135、WO2023045960、WO2023041059、WO2023041059、WO2023 040989、WO2023040513、WO2023039240、WO2023039020、WO2023036282、WO2 023034290、WO2023030517、WO2023030495、WO2023030385、WO2023030495、W O2023030517, WO2023030685, WO2023030687, WO2023034290, WO2023036282, WO2023039240, WO203020347, WO2023025116, WO2023287896, WO20232877 30, WO2023284881, WO2023284730, WO2023284537, WO2023283933, WO2023283213, WO2023280280, WO2023280136, WO2023280026, WO2023278600, WO202 3274383, WO2023327324, WO2023040989, WO2023039240, WO2023039020, WO2023036282, WO2023034290, WO2023030517, WO2023030495, WO2023030385WO2023025116, WO2023020523, WO2023020521, WO2023020519, WO2023020518, WO2023020347, WO2023018812, WO2023018810, WO2023018809, WO20230 18699, WO2023014979, WO2023014006, WO2023004102, WO2023003417, WO2023001141, WO2023001123, WO2022271658, WO2022269508, WO2022266167, W O2022266069, WO2022266015, WO2022265974, WO2022261154, WO2022261154, WO2022251576, WO2022251296, WO2022237815, WO2022232332, WO2022232331, WO2022232320, WO2022232318, WO2022223037, WO2022221739, WO2022221528, WO2022221386, WO2022216762 (e.g., compound 44 or compound 66a), WO2022212 894, WO2022192794, WO2022192790, WO2022188729, WO2022187411, WO2022184178, WO2022173870, WO2022173678, WO2022135346, WO2022133731, WO2 022133038, WO2022133345, WO2022132200, WO2022119748, WO2022109485, WO2022109487, WO2022066805, WO2022002102, WO2022002018, WO202125933 1, WO2021257828, WO2021252339, WO2021248095, WO2021248090, WO2021248083, WO2021248082, WO2021248079, WO2021248055, WO2021245051, WO202 1244603, WO2021239058, WO2021231526, WO2021228161, WO2021219090, WO2021219090, WO2021219072, WO2021218939, WO2021217019, WO2021216770,WO2021215545、WO2021215544、WO2021211864、WO2021190467、WO2021185233、WO2021180181、WO2021175199、2021173923、WO2021169990、WO2021169963、WO2021168193、WO2021158071、WO2021155716、WO2021152149、WO2021150613、WO2021147967、WO2021147965、WO2021143693、WO2021142252、WO2021141628、WO2021139748、WO2021139678、WO2021129824、WO2021129820、WO2021127404、WO2021126816、WO2021126799、WO2021124222、WO2021121371、WO2021121367、WO2021121330、WO2021113595、WO2021107160、WO2021106231、WO2021088458、WO2021086833、WO2021085653、WO2021081212、WO2021058018、WO2021057832、WO2021055728、WO2021031952、WO2021027911、WO2021023247、WO2020259513、WO2020259432、WO2020234103、WO2020233592、WO2020216190、WO2020178282、WO2020146613、WO2020118066、WO2020113071、WO2020106647、WO2020102730、WO2020101736、WO2020097537、WO2020086739、WO2020081282、WO2020050890、WO2020047192、WO2020035031、WO2020028706、WO2019241157、WO2019232419、WO2019217691、WO2019217307、WO2019215203、WO2019213526、WO2019213516、WO2019155399、WO2019150305、WO2019110751、WO2019099524、WO2019051291、WO2018218070、WO2018218071、WO2018218069、WO2018217651、WO20182、 06539, WO2018143315, WO2018140600, WO2018140599, WO2018140598, WO2018140514, WO2018140513, WO2018140512, WO2018119183, WO2018112420, WO2018068017, WO2018064510, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO2017058807, WO2017058805, WO2017058728, WO20170 58902, WO2017058792, WO2017058768, WO2017058915, WO2017015562, WO2016168540, WO2016164675, WO2016049568, WO2016049524, WO2015054572, W O2014152588, WO2014143659, WO2013155223, CN115721720, CN115724842, CN115785124, CN115785199, CN114437084, CN114195788, CN114437107, CN 114409653, CN114380827, CN114195804, CN114057776, CN114057744, CN114057743, CN113999226, CN113980032, CN113980014, CN113960193, CN113 929676, CN113754653, CN113683616, CN113563323, CN113527299, CN113527294, CN113527293, CN113493440, CN113429405, CN113248521, CN1133216 54, CN113087700, CN113024544, CN113004269, CN112920183, CN112778284, CN112390818, CN112390788, CN112300196, CN112300194, CN112300173, CN112225734, CN112142735, CN112110918, CN112094269, CN112047937, and CN109574871, or CN117683051, CN117645627, CN117624194, CN117624190,CN117586280、CN117486901、CN117466917、CN117462688、CN117362315、CN117327102、CN117327094、CN117327074、CN117285590、CN117263959、CN117247382、CN117186095、CN117164605、CN116969977、CN116925075、CN116891489、CN116731045、CN116731044、CN116554208、CN116514846、CN116478184、CN116478141、CN116410145、CN116375742、CN116354988、CN116332948、CN116332938、CN116327956、CN116262759、CN116217592、CN116199703、CN116162099、CN116143806、CN116143805、CN116120315、CN116102559、CN115960105、CN115894520、CN115872979、CN115850267、CN115785199、CN115785124、CN115785124、CN115724842、CN115716840、CN115703775、CN115611923、CN115611898、CN115583937、CN115572278、CN115557949、CN115521312、CN115504976、CN115490709、CN115466272、CN115433183、CN115433179、CN115403575、CN115385938、CN115385937、CN115385912、CN115381786、CN115368383、CN115368382、CN115368381、CN115353506、CN115322158、CN115304623、CN115304602、CN115197245、CN115181106、CN114989195、CN114989166、CN114989147、CN114920741、CN114920739、CN114907387、CN114874234、CN114874201、CN114716436、CN114716435、CN114685532、CN114685460、CN114591319, CN114539293, CN114539286, CN114539246, CN114437107, CN114437084, CN114409653, CN114380827, CN114195804, CN114195788, CN114057776, CN114057744, CN114057743, CN113999226, CN113980032, CN113980014, CN113929676, CN113754653, CN113683616, CN113563323, CN113527299, CN113527294, CN113527293, CN113493440, CN113429405, CN113248521, CN113087700, CN113024544, CN113004269, CN112920183, CN112778284, CN112390818, CN112390788, CN112300196, CN112300194, CN112300173, CN112225734, CN112142735, CN112110918, CN112094269, CN112047937, and CN109574871, each of these, including the structure of the RAS compound disclosed in the said document, is incorporated herein by reference, in particular.

[0099] In any embodiment of this specification using an RAS(OFF) inhibitor, RAS(OFF) degrading agents targeting the OFF state of the RAS may be used as an alternative. These degrading agents are known in the art. RAS degrading agents may be found, for example, in one or more of the following applications: WO2024083258, WO2024083256, WO2024055112, WO2024054625, WO2024050742, WO2024044334, WO2024040080, WO2024034657, WO2024034593, WO2024034591, WO2024034123, WO2024029613, WO202 4020159, WO2024019103, WO2024017392, WO2023185864, WO2023171781, WO2023141570, WO2023138524, WO2023130012, WO2023116934, WO2023099620, WO2023081476, WO2023077441, and CN115785199, each of these in whole, are incorporated herein by reference.

[0100] In some embodiments, RAS(OFF) inhibitors are peptide-based inhibitors. For example, peptide-based RAS(OFF) inhibitors have been developed that target specific regions of the RAS protein, such as the switch II region or the RAS effector interface. Non-limiting examples include the K-Ras binding peptide (Krpep-2d), the Ras inhibitor peptide (RasIn), and LUNA18 (NCT05012618). Peptide-based RAS(OFF) inhibitors are a class of compounds that target the RAS protein by interfering with its interaction with downstream effectors or other signaling proteins. These inhibitors are typically designed to mimic the binding motif of RAS interacting proteins or other RAS effectors, such as RAF or PI3K. By binding to RAS at the same site as these effectors, peptide-based inhibitors can effectively compete with these proteins and block the activation of downstream signaling pathways.

[0101] Peptide-based RAS(OFF) inhibitors can be further classified into two main categories: those targeting the RAS-effector interface and those targeting other regions of the RAS protein. Peptide-based inhibitors targeting the RAS-effector interface are designed to bind to the switch region of RAS, which is important in interactions with downstream effectors such as RAF or PI3K. These inhibitors typically contain amino acid residues similar to those found in the binding motif of RAS-interacting proteins or effectors, and are often designed to form hydrogen bonds or other interactions with key residues on the RAS surface.

[0102] Peptide-based RAS(OFF) inhibitors that target other regions of the RAS protein are typically designed to interfere with other interactions that are important for RAS activation or signaling. For example, some peptide-based inhibitors are designed to bind to the hypervariable region of the RAS, which is thought to play a role in protein membrane localization and fixation. By binding to this region, peptide-based inhibitors may block the proper localization of the RAS to the plasma membrane, which is necessary for activation and signaling.

[0103] Several common motifs have been identified as important for the binding of RAS-interacting proteins and effectors and are often used in the design of peptide-based inhibitors. One example is the RAF-binding domain (RBD), found in many RAS-interacting proteins and important for the interaction between RAS and downstream effectors such as RAFs. The RBD contains a conserved amino acid sequence (Arg-Xaa-Arg) that is important for binding to RAS, and this motif has been incorporated into several peptide-based inhibitors designed to disrupt RAS-RAF interactions. Another example is the RAS-binding domain (RBD) of PI3K, which is important for the interaction between RAS and its downstream effector. The PI3K RBD contains several conserved amino acid residues (such as Arg-Arg-Trp) that are important for binding to RAS, and these motifs have been used in the design of peptide-based inhibitors targeting RAS-PI3K interactions. Other common motifs used in peptide-based RAS(OFF) inhibitors include sequences that mimic the structure of the Ras-binding domain (RBD) of other RAS-interacting proteins such as RalGDS and SOS, as well as the switch region of RAS itself. These motifs are typically used to optimize the binding affinity and selectivity of the inhibitor for a desired target protein or interaction.

[0104] In some embodiments, RAS(OFF) inhibitors are antibodies or antigen-binding peptides specific to RAS(OFF). For example, antibodies have been developed that bind to specific regions of the RAS protein, such as the switch II region or the RAS effector interface. For instance, several antibodies have been developed that target the switch region of the RAS protein, which is crucial for the activation of these proteins and their interaction with downstream effectors. By binding to the switch region, these antibodies can block the conformational changes necessary for RAS activation and downstream signaling. Another approach involves the use of antibodies that target RAS-interacting proteins or downstream effectors, such as RAF or PI3K. By binding to the target protein, these antibodies can disrupt the RAS-dependent signaling pathway, potentially inhibiting the proliferation and survival of cancer cells. Furthermore, several antibodies have been developed that can induce the internal translocation and degradation of RAS proteins, leading to their depletion and inhibition of downstream signaling. For example, several antibodies have been developed that recognize the unique structures of mutant RAS proteins and target them for degradation via the ubiquitin-proteasome pathway. Non-specific examples of KRAS(OFF)-specific inhibitory antibodies include anti-p21ser and K27(DARPin) (see, for example, Khan et al, Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118570).

[0105] ii) SOS1 inhibitors In some embodiments, the compositions and methods described herein may include one or more RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more SOS1 inhibitors. The SOS1 inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the SOS1 inhibitors are one or more of RMC-5845, RMC-4948, RMC-0331, BI-1701963, BI-3406, SDR5, MRTX-0902, and BAY-293. In some embodiments, references to the term SOS1 inhibitor include any such SOS1 inhibitor disclosed in any one of the following patent applications: WO2023029833, WO2023041049, WO2023022497, WO2022184116, WO2022170952, WO2022170917, WO2022171184, WO2022170802, WO2022161 461, WO2022121813, WO2022028506, WO2022139304, WO2021228028, WO2019122129, CN115215847, CN115028644, CN114685488, CN111393519, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0106] iii) SHP inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more SHP inhibitors. The SHP inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the SHP inhibitor is an inhibitor of SHP1. In some embodiments, the SHP inhibitor is an inhibitor of SHP2. In some embodiments, the SHP1 inhibitor is SB6299, also known as DA-4511. In some embodiments, the SHP2 inhibitor is one or more of SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, or BBP-398. In some embodiments, references to the term SHP2 inhibitor include any such SHP2 inhibitor disclosed in any one of the following patent applications: WO2023282702, WO2023280283, WO2023280237, WO2023018155, WO2023011513, WO202227196. 6, WO2022271964, WO2022271911, WO2022259157, WO2022242767, WO2022241975, WO20222 37676, WO2022237367, WO2022237178, WO2022235822, WO20222084008, WO2022135568, WO 2022063190, WO2022043865, WO2022042331, WO2022033430, WO2022017444, WO202200786 9, WO2021259077, WO2021249449, WO2021249057, WO2021244659, WO2021218755, WO20211 76072, WO2021171261, WO2021149817, WO2021148010, WO2021147879, WO2021143823, WO2 021143701, WO2021143680, WO2021281752, WO2021121397, WO2021119525, WO2021115286,WO2021110796、WO2021088945、WO2021073439、WO2021061706、WO2021061515、WO2021043077、WO2021033153、WO2021028362、WO2021033153、WO2021028362、WO2021018287、WO2020259679、WO2020249079、WO2020210384、WO2020201991、WO2020181283、WO2020177653、WO2020165734、WO2020165733、WO2020165732、WO2020156243、WO2020156242、WO2020108590、WO2020104635、WO2020094104、WO2020094018、WO2020081848、WO2020073949、WO2020073945、WO2020072656、WO2020065453、WO2020065452、WO2020063760、WO2020061103、WO2020061101、WO2020033828、WO2020033286、WO2020022323、WO2019233810、WO2019213318、WO2019183367、WO2019183364、WO2019182960、WO2019167000、WO2019165073、WO2019158019、WO2019152454、WO2019051469、WO2019051084、WO2018218133、WO2018172984、WO2018160731、WO2018136265、WO2018136264、WO2018130928、WO2018129402、WO2018081091、WO2018057884、WO2018013597、WO2017216706、WO2017211303、WO2017210134、WO2017156397、WO2017100279、WO2017079723、WO2017078499、WO2016203406、WO2016203405、WO2016203404、WO2016196591、WO2016191328、WO2015107495、WO2015107494、WO2015107493、WO2014176488、WO2014113584、CN115677661、CN115677660, CN115611869, CN115521305, CN115490697, CN115466273, CN115394612, C N115304613, CN115304612, CN115300513, CN115197225, CN114957162, CN114920759, CN1 14716448, CN114671879, CN114539223, CN114524772, CN114213417, CN114195799, CN11 4163457, CN113896710, CN113248521, CN113248449, CN113135924, CN113024508, CN1129 20131, CN112823796, CN112409334, CN112402385, CN112174935, 111848599, CN111704611, CN111393459, CN111265529, CN110143949, CN108113848, US11179397, US11044675, US11034705, US11033547, US11001561, US10988466, US10954243, US10934302, or US10858359, each of these, including the compound structure disclosed in the said document, is specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0107] iv) MEK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more MEK inhibitors. The MEK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the MEK inhibitor is one or more of pimacertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation that is a class I MEK1 mutation selected from D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N. In some embodiments, reference to the term MEK inhibitor includes any such MEK inhibitor disclosed in any one of the following patent applications: WO2022221866, WO2022125941, WO2022208391, WO2022015736, WO2022177557, WO2021018866, WO2021069486, WO2021142144, WO2021168283, WO2021 234097, WO2019076947, WO2018233696, WO2016188472, WO2014063024, WO2013019906, WO2011047238, WO2007044515, US2023032403, and CN115813930, each of these, including the compound structures disclosed in the said documents, are incorporated herein by reference in their entirety.

[0108] v) RAF inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more RAF inhibitors. The RAF inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the RAF inhibitor is VS-6766. In some embodiments, the RAF inhibitor is a BRAF inhibitor. Examples of BRAF inhibitors that can be used in combination with the RAS(ON) inhibitor include Vs6766, IK-595, vemurafenib, dabrafenib, and encorafenib. BRAF may include class 3 BRAF mutations. In some embodiments, a class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H, P367R, V459L, G466V, G466E, G466A, S467L, G469E, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, G596R, and A762E. In some embodiments, references to the term RAF inhibitor include any such RAF inhibitor disclosed in any one of the following patent applications: WO2022226626, WO2022226261, WO2019084459, WO2018203219, WO2017212442, WO2015075483, WO2013134243, WO2013134298, WO2011047238, WO2011025965, WO20110 25947, WO2011025951, WO2011025940, WO2011025938, WO2010065893, WO2009016460, WO2009130015, WO2009111278, WO2009111279, WO2008028141, and WO2006024834, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0109] (co) ERK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more ERK inhibitors. The ERK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the ERK inhibitor is an ERK1 / 2 inhibitor such as ERAS-007. In some embodiments, the ERK inhibitor is an ERK5 inhibitor. In some embodiments, the ERK inhibitor is one or more of ASTX-029 or I-75. In some embodiments, references to the term ERK inhibitor include any such ERK inhibitor disclosed in any one of the following patent applications: WO2021110169, WO2021110168, WO2021252316, WO2020102686, WO2020228817, WO2020107987, WO2019233456, WO2019233457, WO2016025561, WO2016192063, WO201 6106029, WO2016106009, WO2015051341, WO2014124230, WO2014052563, WO2011041152, WO200910550, WO2008153858, CN114315837, CN115057860, and CN107973783, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of these documents is incorporated herein by reference.

[0110] vii) MAPK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more mitogen-activated protein kinase (MAPK) inhibitors. The MAPK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the MAPK inhibitor is a p38-MAPK inhibitor or a MAP3K8 inhibitor. In some embodiments, the MAPK inhibitor is one or more of chilpicertive (GS-4875) and neframapidomod (VX-745). In some embodiments, references to the term MAPK inhibitor include any such MAPK inhibitor disclosed in any one of the following patent applications: WO2016029263, CN114767674, CN115850179, and CN1743006, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0111] In some embodiments, therapeutic agents that can be combined with RAS(ON) inhibitors are MAP2K4 inhibitors. A non-limiting example of a MAP2K4 inhibitor useful according to this disclosure is HRX-0233.

[0112] c) Kinase inhibitors The compositions and methods described herein may include RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more kinase inhibitors. Tyrosine kinases and serine / threonine kinases play important roles in various cellular processes such as cell signaling, proliferation, and differentiation. Kinase inhibitors known in the art have been developed as therapies for various types of cancer, in addition to therapies for conditions such as neurodegenerative diseases, autoimmune diseases, and inflammation.

[0113] i) PKA inhibitors In some embodiments, the compositions and methods described herein may comprise one or more protein kinase A (PKA) inhibitors. The PKA inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the PKA inhibitor is H89. In some embodiments, references to the term PKA inhibitor include any such PKA inhibitor disclosed in any one of the following patent applications: CN106620678 and CN114632155, each of which comprises the compound structure disclosed in said document, which is specifically incorporated herein by reference.

[0114] ii) FAK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more focal adhesion kinase (FAK) inhibitors. The FAK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the FAK inhibitor is one or more of BI853520, defactinib, GSK2256098, PF-00562271, and VS-4718. In some embodiments, references to the term FAK inhibitor include any such FAK inhibitor disclosed in any one of the following patent applications: WO2022152315, WO2021098679, WO2020135442, WO2020191448, WO2012022408, WO2013134353, WO2012110774, WO2010062578, CN111072571, and KR101691536, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0115] iii) ROCK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more Rho-related coiled-coil-containing protein kinase (ROCK) inhibitors. The ROCK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the ROCK inhibitor is GSK269962A. In some embodiments, references to the term ROCK inhibitor include any such ROCK inhibitor disclosed in any one of the following patent applications: WO2023051753, WO2022237892, WO2022012409, WO2021093795, WO2021214200, WO2020177292, WO202011751, WO2019014304, WO2019179525, WO2019089868, WO2019014300, WO2018108156, WO2018009627, WO2018009625, WO2018009622, WO2017123860, W O2017205709, WO2016112236, WO2014068035, WO2013030367, WO2012146724, WO2012067965, WO2011107608, CN108129453, CN108191821, CN110917352, CN108558823, CN108047193, CN107973777, CN108047197, CN108129448, CN115869304, and GB202214708, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0116] iv) MSK1 inhibitors In some embodiments, the compositions and methods described herein may include one or more mitogens and stress-activated kinase (MSK1) inhibitors combined with RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805). The MSK1 inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the MSK1 inhibitors are one or more of SB-747651A, SB747651A, Ro320432, CGP57380, GSK2830371, SR1664, LY-3214996, PFI-4, MSC-2363318A, and AS601245.

[0117] v) RSK inhibitors In some embodiments, the compositions and methods described herein may include one or more ribosomal S6 kinase (RSK) inhibitors combined with RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805). The RSK1 inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the RSK inhibitor is one or more of BI-D1870, LJH685, SL0101-1, FMK, BRD7389, BIX02565, LJI308, LJI308-S, LJI308-1, and LJH685-S. In some embodiments, the RSK inhibitor is PMD-026. In some embodiments, references to the term RSK inhibitor include any such RSK inhibitor disclosed in any one of the following patent applications: WO2021249558, WO2020165646, WO2017141116, and CN113801139, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0118] vi) ALK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more anaplastic lymphoma kinase (ALK) inhibitors. The ALK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the ALK inhibitor is one or more of the following: crizotinib (Zalkoli), ceritinib (Zykadia), alectinib (Alecensa), brigatinib (Alumbrig), lorlatinib (Lorbrena), ensartinib (X-396), TAE684, ASP3026, TPX-0131, LDK378 (ceritinib analog), CEP-37440, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. 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 one of the following patent applications: WO2019142095, WO2019179482, WO2018130928, WO2018127184, WO2017101803, WO2016192132, WO2014100431, WO2012082972, CN111138492, CN110526914, CN109836415, CN105801603, CN107987056, and CN105878248, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0119] d) Receptor tyrosine kinase inhibitors The compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more receptor tyrosine kinase inhibitors. Receptor tyrosine kinase (RTK) inhibitors are a type of molecule (e.g., small molecules, antibodies, and nucleic acids) that binds to receptor tyrosine kinases or their ligands and blocks their activity. RTKs are proteins found on the surface of cells and play important roles in cell signaling and proliferation, and have been developed as therapeutic agents for a variety of diseases, including cancer, diabetes, and autoimmune disorders. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor such as afatinib.

[0120] i) EGFR inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more EGFR inhibitors. The EGFR inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zaltumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its native ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br.J. Cancer 1993, 67:247-253, Teramoto et al., Cancer 1996, 77:639-645, Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318, Huang et al., 1999, Cancer Res. 15:59(8):1935-40, and Yang et al., Cancer Res. 1999, 59:1236-1243. EGFR inhibitors can be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999), or Mab C225 (ATCC accession number HB-8508), or antibodies or antibody fragments having binding specificity thereto.

[0121] Small molecule antagonists of EGFR include gefitinib (Iressa®), razertinib, erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8, and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). In some embodiments, the EGFR inhibitor is one or more of cetuximab, gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Girotrif). Further non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. The EGFR inhibitor may be ERAS-801. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family includes HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4). In some embodiments, the EGFR inhibitor may be bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, ruxolitinib, sunitinib, vemurafenib, abrocitinib, aciminib, futivatinib, ibrutinib, imatinib, pacritinib, or sorafenib. In some embodiments, references to the term EGFR inhibitor include any such EGFR inhibitor disclosed in any one of the following patent applications: WO2023041071, WO2023049312, WO2023020600,WO2023284747, WO2022206797, WO2022258977, WO2022033416, WO2022033410, WO2022105908, WO2022100641, WO2022014639, WO2022007841, WO202 1018009, WO2021057882, WO2021252661, WO2021018003, WO2021073498, WO2021238827, WO2020254547, WO2020216371, WO2020147838, WO202020748 3, WO2020254572, WO2020001350, WO2021001351, WO2019164948, WO2019218958, WO2019046775, WO2019015655, WO2018121758, WO2018218963, WO2 017220007, WO2017205459, WO2017161937, WO2016192609, WO199633980, WO199630347, WO199730034, WO199730044, WO199738994, WO199749688, WO 199802434, WO199738983, WO199519774, WO199519970, WO199713771, WO199802437, WO199802438, WO199732881, WO199833798, WO199732880, WO19 9732880, WO199702266, WO199727199, WO199807726, WO1997 / 34895, WO199631510, WO199814449, WO199814450, WO199814451, WO199509847, WO1997 19065, WO199817662, WO199935146, WO199935132, WO199907701, WO199220642, DE19629652, EP682027, EP837063, EP0787772, EP0520722, EP0566226, CN115960018, CN110283162, CN114044774, CN111973601, CN111973602, and CN113896744, each of these, includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.The entire text is incorporated herein by reference.

[0122] ii) HER2 inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more HER2 inhibitors. The HER2 inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the HER2 inhibitor is one or more of tucatinib, rastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), adtrastuzumab emtansine (Kadcyla), and neratinib (Nerlinks). Non-exclusive examples of HER2 inhibitors include monoclonal antibodies, such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa®), erlotinib (Tarceva®), pyritinib, CP-654577, CP-724714, canertinib (CI1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW2992, ARRY-334543, and JNJ-26483327. In some embodiments, references to the term HER2 inhibitor include any such HER2 inhibitor disclosed in any one of the following patent applications: WO2021156178, WO2021156180, WO2021213800, WO2021088987, WO2013561183, and WO2013056108, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0123] iii) MET inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more MET inhibitors. The MET inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the MET inhibitor is one or more of crizotinib (Zalkoli), cabozantinib (Cometriq, Cabometyx), capmatinib (Tabrecta), tepotinib (Tepmetco), savolitinib (Volitinib), onartuzumab (MetMab), foretinib (GSK1363089), MGCD-265 (Amvatinib), SU11274, and SU5416. In some embodiments, references to the term MET inhibitor include any such MET inhibitor disclosed in any one of the following patent applications: WO2022226168, WO2021222045, WO2020047184, WO2020015744, WO2020244654, WO2020156453, WO2019206268, WO2018077227, WO2017012539, WO2016015653, WO2016012963, WO201201567 7, WO2011162835, WO2010089507, WO2009091374, WO2009056692, WO2008051547, WO2007130468, US2012237524, CN103497177, CN107311983, CN107382968, CN110218191, and TW201331206, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0124] iv) AXL inhibitors In some embodiments, the compositions and methods described herein may include one or more RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more AXL inhibitors. The AXL inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. AXL is a receptor tyrosine kinase belonging to the TAM family of receptors, which also includes TYRO3 and MERTK. In some embodiments, the AXL inhibitor is one or more of vemcentib, BGB324, R428, SGI-7079, TP-0903, BMS-777607, UNC2025, and TP-0903. In some embodiments, references to the term AXL inhibitor include any such AXL inhibitor disclosed in any one of the following patent applications: WO2023045816, WO2022237843, WO2022246179, WO2021012717, WO2021088787, WO2021067772, WO2021239133, WO2021204713, WO2020238802, WO2019 039525, WO2019101178, WO2019074116, WO2017146236, WO2016097918, WO2015012298, WO2010005876, WO2010083465, CN115073367, and JP2022171109, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0125] v) IGFR inhibitors In some embodiments, the compositions and methods described herein may include one or more RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more insulin-like growth factor receptor 1 (IGF-1R) inhibitors. The IGFR inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. IGFR inhibitors have been developed to target the IGFR receptor, which plays a critical role in cancer progression and metastasis. In some embodiments, the IGFR inhibitor is one or more of lincitinib, AXL1717, OSI-906 (lincitinib), BMS-754807, BI836845, AZ12253801, PQIP (pyrrolo[1,2-a]quinoxaline), and NVP-AEW541. In some embodiments, references to the term IGFR inhibitor include any such IGFR inhibitor disclosed in any one of the following patent applications: WO2022115946, WO2022217923, WO2021203861, WO2021246413, WO2020116398, WO2019046600, WO2018195250, WO2018221521 WO2018204872, WO2017072196, WO2016173682, WO2015162291, WO2015162292, WO2010066868, WO2006069202, and CN112125916, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0126] vi) RET inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) combined with a rearranged (RET) inhibitor during one or more transfections. The RET inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. RETs play important roles in various cellular processes, including cell proliferation, differentiation, survival, and migration. RETs are activated by binding to their ligands, such as ligands of the glial cell line-derived neurotrophic factor (GDNF) family, which leads to the activation of downstream signaling pathways that facilitate these cellular processes. In some embodiments, the RET inhibitor is one or more of the following: pralcetinib, serpercatinib (LOXO-292), BLU-667, RXDX-105, TPX-0046, GSK3179106, molydastat (BAY85-3934), and RPI-1 (retrofin). In some embodiments, references to the term RET inhibitor include any such RET inhibitor disclosed in any one of the following patent applications: WO2021211380, WO2021057963, WO2021043209, WO2021222017, WO2020035065, WO2020114487, WO2020200314, WO2020200316, WO2020114494, WO2018071447, WO2018213329, WO2017079140, W O2014050781, CN113943285, CN113683610, CN113683611, CN113620944, CN113620945, CN113527291, CN113527292, CN113527290, CN113135896, CN111057075, CN111233899, and CN111362923, each of these, including the compound structure disclosed in the said document, is specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0127] vii) ROS1 inhibitors In some embodiments, the compositions and methods described herein may include one or more RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more c-ros oncogene 1 (ROS1) inhibitors. The ROS1 inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. ROS1 is a receptor tyrosine kinase belonging to the insulin receptor family and plays a role in various cellular processes, including cell proliferation, differentiation, survival, and migration. In some embodiments, the ROS1 inhibitor is one or more of taretrectinib, DS-6051b, TPX-0131, GZD824, and PF-06463922. In some embodiments, references to the term ROS1 inhibitor include any such ROS1 inhibitor disclosed in any one of the following patent applications: WO2021098703, WO2020024825, and US2017079972, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0128] viii) PDGFR inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more platelet-derived growth factor receptor (PDGFR) inhibitors. The PDGFR inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. PDGFR is a family of receptor tyrosine kinases consisting of two members, PDGFRα and PDGFRβ. They are activated by binding to their ligands, such as platelet-derived growth factor (PDGF), which leads to the activation of downstream signaling pathways that promote cell growth, proliferation, and survival. In some embodiments, the PDGFR inhibitor is one or more of CP-673451, imatinib, nintedanib (Ofev), sunitinib (Stent), pazopanib (Botrian), regorafenib (Stivarga), and dasatinib (Sprycel).

[0129] ix) FGF inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with a fibroblast growth factor (FGF) inhibitor. The FGF inhibitor may be administered or formulated in combination with the RAS inhibitor described herein and / or any additional therapeutic agent. FGFR is a family of receptor tyrosine kinases consisting of four members, FGFR1-4. FGFRs are activated by binding to their ligand, fibroblast growth factor (FGF), which leads to the activation of downstream signaling pathways that promote cell proliferation, differentiation, and survival. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR2. In some embodiments, the FGFR inhibitor is an inhibitor of FGFR4. In some embodiments, the FGFR inhibitor is one or more of the following: futivatinib (TAK-659), erdafitinib (Barvasa), infiglatinib (Truseltiq), Debio1347, and logaratinib (BAY1163877). In some embodiments, references to the term FGFR inhibitor include any such FGFR inhibitor disclosed in any one of the following patent applications: WO2022033472, WO2022152274, WO2022166469, WO2022206939, WO2021037219, WO2021089005, WO2021113462, WO2020185532, WO2019213544, WO2020164603, WO2019154364, WO2019034076, WO2019213506, WO2019223766, WO2 018028438, WO2018153373, WO2018121650, WO2018010514, WO2017028816, WO2017118438, WO2016134320, WO2015008844, WO2014172644, WO2014007951, WO2013179033, WO2013087578, WO2012047699, CN105906630, CN115869315, CN115141176, CN115043832, and CN115028634, each of these in whole is incorporated herein by reference.In some embodiments, FGF pathway inhibitors target FGF ligands. Such FGF pathway inhibitors include FGF ligand traps and antibodies. Non-limiting examples include FP-1039, an FGF ligand trap consisting of the extracellular domain of FGFR1 fused to the Fc portion of human IgG1, designed to sequester FGF ligands and inhibit FGF signaling, and MFGR1877S, a monoclonal antibody targeting FGF ligands, designed to block FGF-mediated signaling, including the compound structures disclosed herein, which are specifically incorporated herein by reference.

[0130] x) VEGF inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more vascular endothelial growth factor (VEGF) signaling inhibitors. VEGF (vascular endothelial growth factor) signaling inhibitors are a class of drugs that target signaling pathways mediated by VEGF and its receptors. VEGF plays a crucial role in angiogenesis, the process of forming new blood vessels from existing ones, and is overexpressed in many types of cancer, making it an attractive target for cancer treatment. VEGF inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the VEGF inhibitor is an antibody or antigen-binding domain that specifically binds to VEGF (e.g., bevacizumab), or a soluble VEGF receptor or its ligand-binding domain, e.g., VEGF-TRAP®, and an anti-VEGF receptor agent (e.g., an antibody or antigen-binding domain that specifically binds to it). In some embodiments, the VEGF inhibitor is one or more of bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, and pazopanib.

[0131] e) PI3K / mTOR pathway inhibitors The compositions and methods described herein may include RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more inhibitors of the PI3K-AKT-TOR signaling pathway. The PI3K-AKT-mTOR signaling pathway is a critical intracellular pathway that controls a wide range of cellular processes, including cell proliferation, growth, metabolism, and survival. This pathway is initiated when growth factors such as insulin or IGF-1 bind to cell surface receptors and activate phosphoinositide 3-kinase (PI3K). The activated PI3K then phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to produce phosphatidylinositol 3,4,5-trisphosphate (PIP3), which then activates AKT. Activated AKT activates mTOR (mammalian target of rapamycin) complex 1 (mTORC1) by phosphorylating various downstream targets, including the tuberous sclerosis complex (TSC1 / TSC2). 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).

[0132] i) PI3K inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more PI3K inhibitors. The PI3K inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents.PI3K inhibitors include wartmannin, 17-hydroxywartmannin analog described in WO06 / 044453, 4-[2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)piperazine-1-yl]methyl]thieno[3,2-d]pyrimidine-4-yl]morpholine (also known as pictilisib or GDC-0941, described in WO09 / 036082 and WO09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4 ,5-c]quinoline-1-yl]phenyl]propionitrile (also known as BEZ235 or NVP-BEZ235, described in WO06 / 122806), (S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740), LY294002(2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (Axon (Available from Medchem), PI103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]fl[3,2-d]pyrimidine-2-yl]phenol hydrochloride (Available from Axon Medchem), PIK75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridine-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (Available from Axon Medchem), PIK90 (N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-nicotinamide (Axon This includes, but is not limited to, AS-252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidined-2,4-dione (available from Axon Medchem), TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrinidine-4-one (available from Axon Medchem), XL-765, and XL-147.Other PI3K inhibitors include demethoxypyridine, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, paromide 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136. In some embodiments, the PI3K inhibitor is alpelisib or copanlisib.

[0133] ii) AKT inhibitors In some embodiments, the compositions and methods described herein may include one or more AKT inhibitors combined with RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805). The AKT inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. AKT inhibitors include ipatasertib, GSK-2141795, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem.J.2005,385(Pt.2):399-408), Akt-1-1,2 (inhibits Akl and 2) (Barnett et al., Biochem.J.2005,385(Pt.2):399-408), API-59CJ-Ome (e.g., Jin et al., Br.J.Cancer 2004,91:1808-12), 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05 / 011700), indole-3-carbinol and its derivatives (e.g., U.S. Patent No. 6,656,963, Sarkar and Li J. This includes, but is not limited to, Nutr.2004,134(12 Suppl):3493S-3498S, perifosine (e.g., Dasmahapatra et al. Clin. Cancer Res.2004,10(15):5242-52), phosphatidylinositol ether lipid analogs (e.g. Gills and Dennis Expert. Opin. Investig. Drugs 2004,13:787-97), and trisirivine (TCN or API-2 or NCI discriminant: NSC154020; Yang et al., Cancer Res.2004,64:4394-9). PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors listed in Cancers (Basel) 2015 Sep;7(3):1758-1784.For example, PI3K / AKT inhibitors may be selected from one or more of the following: NVP-BEZ235, BGT226, XL765 / SAR245409, SF1126, GDC-0980, PI-103, PF-04691502, PKI-587, and GSK2126458.

[0134] iii) mTOR inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more mTOR inhibitors. The mTOR inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. mTOR inhibitors include ATP-competitive mTORC1 / mTORC2 inhibitors, e.g., PI-103, PP242, PP30; Torin1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, e.g., temsirolimus (Torisel®); everolimus (Afinitor®, WO94 / 09010); and Ridafo Rolimus (also known as deforolimus or AP23573); rapamycin, e.g., as disclosed in WO98 / 02441 and WO01 / 14387, e.g., AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolite)- Rapamycin (also known as ABT578); 32-deoxorapamycin; 16-pentinyloxy-32(S)-dihydrolapanisin; derivatives disclosed in WO05 / 005434; U.S. Patents Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and WO Examples include, but are not limited to, derivatives disclosed in 94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018204416, as well as phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252).In some embodiments, the mTOR inhibitor is a disteric inhibitor such as RMC-5552 (see, for example, WO2018204416, WO2019212990, and WO2019212991).

[0135] iv) MNK inhibitors In some embodiments, the compositions and methods described herein may comprise a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more mitogen-activated protein kinase interaction kinase (MNK) inhibitors. The MNK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. The MNK protein is activated downstream of the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a crucial role in regulating cell proliferation, differentiation, and survival. MNK phosphorylates eIF4E, a key component of the eukaryotic translation initiation complex that enhances the translation of certain mRNAs, including those encoding proteins involved in cell cycle regulation and oncogenesis. In some embodiments, the MNK inhibitors are one or more tomibocertib (eFT508), CGP57380, and SEL201. In some embodiments, references to the term MNK inhibitor include any such MNK inhibitor disclosed in any one of the following patent applications: WO2021098691, WO2020108619, WO2020086713, WO2018152117, WO2018228275, WO2015200481, and CN115583942, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0136] v) eIF4 inhibitors In some embodiments, the compositions and methods described herein may include one or more eukaryotic initiation factor 4A (eIF4A) inhibitors combined with RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805). The eIF4A inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. eIF4A is a key component of the eukaryotic translation initiation complex and functions as an RNA helicase that unwinds the secondary structure of mRNA and promotes ribosome binding. eIF4A is required for the translation of many cancer-related genes and is an attractive therapeutic target for cancer treatment. In some embodiments, the eIF4A inhibitors are one or more zotatifine (eFT226), silvestrol, patheamine A, and locagrate. In some embodiments, references to the term eIF4A inhibitor include any such eIF4A inhibitor disclosed in any one of the following patent applications: WO2023034813, WO2021195128, and WO2017091585, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0137] In some embodiments, the compositions and methods described herein may comprise one or more eukaryotic initiation factor 4G (eIF4G) inhibitors. The eIF4G inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. The eIF4G family comprises several proteins involved in the initiation of protein translation. eIF4G acts as a scaffold for other proteins, including eIF4E and eIF4A, to form the eIF4F complex, which binds to the 5' cap of mRNA and plays a role in unwinding the secondary structure of mRNA to enable ribosome scanning and translation initiation. In some embodiments, the eIF4G inhibitors are one or more patheamine A and hypristanol.

[0138] f) DNA damage response inhibitors The compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more DNA damage response (DDR) inhibitors. The DDR pathway is a critical cellular pathway activated in response to DNA damage and is essential for maintaining genomic stability and thereby preventing the development of cancer. However, cancer cells often have defects in the DDR pathway, making them more sensitive to DDR inhibitors. DDR inhibitors have shown promise in preclinical studies as potential cancer therapies, particularly in combination with other agents.

[0139] i) Wee1 inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more Wee1 inhibitors. Wee1 is a kinase that plays a crucial role in regulating the cell cycle by inhibiting the activity of cyclin-dependent kinases (CDKs) and blocking cell progression through the G2 / M checkpoint. Wee1 is overexpressed in several cancer types and is involved in tumor growth and survival. In some embodiments, the Wee1 inhibitor is one or more of imp7068, adavocertib, or ZNL-02-096. In some embodiments, references to the term Wee1 inhibitor include any such Wee1 inhibitor disclosed in any one of the following patent applications: WO2022011391, WO2022247641, WO2021043152, WO2020221358, WO2020083404, WO2020192581, WO2019085933, WO2018133829, WO2015115355, WO2015183776, WO2014085216, and CN114831993. Each of these includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0140] ii) CHK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more checkpoint kinase (CHK) inhibitors. The CHK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. CHK1 kinase is a key regulator of the cell cycle and DNA damage response pathways. In some embodiments, the CHK inhibitor is a CHK1 inhibitor. In some embodiments, the CHK inhibitor is a CHK2 inhibitor. In some embodiments, the CHK1 inhibitor is one or more ravellintib, LY2606368, GDC-0575, and MK-8776. In some embodiments, references to the term CHK1 inhibitor include any such CHK1 inhibitor disclosed in any one of the following patent applications: WO2021113661, WO2021104461, WO2019012030, WO2010118390, WO2008067027, WO2002070494, and TW202126818, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0141] iii) ATM inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more ataxia telangiectasia mutation (ATM) inhibitors. The ATM inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. ATMs play a role in regulating the replication stress response and maintaining genomic stability. In some embodiments, the ATM inhibitors are one or more M4076, AZD0156, KU-60019, and VE-821. In some embodiments, references to the term ATM inhibitor include any such ATM inhibitor disclosed in any one of the following patent applications: WO2021197339, WO2021098734, WO2021260580, WO2007026157, WO2006085067, and US2016113935, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0142] iv) ATR inhibitors In some embodiments, the compositions and methods described herein may include one or more RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more ataxia telangiectasia and Rad3-related (ATR) inhibitors. The ATR inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the ATR inhibitors are one or more ceraraerutib, VE-821, RP-350, AZ20, VX-970, abd110, VX-803, and BAY1895344. In some embodiments, references to the term ATR inhibitor include any such ATR inhibitor disclosed in any one of the following patent applications: WO2023016529, WO2022237875, WO2022268025, WO2021012049, WO2021023272, WO2021260579, WO2021228758, WO2019 050889, WO2019154365, WO2019133711, WO2017059357, WO2013049859, WO2007046426, WO2007015632, and CN113797341, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of these documents is incorporated herein by reference.

[0143] v) PARP inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more poly(ADP-ribose) polymerase (PARP) inhibitors. Seventeen members of the PARP (also known as tankirase) family have been identified. PARP enzymes play a crucial role in DNA damage repair, particularly in the repair of single-strand DNA breaks. PARP inhibitors block the activity of PARP enzymes, leading to the accumulation of DNA damage and ultimately cell death. In some embodiments, the PARP inhibitors are one or more olaparib, lucaparib, niraparib, and veliparib (ABT-888).In some embodiments, references to the term PARP inhibitor include any such PARP inhibitor disclosed in any one of the following patent applications: WO2023051812, WO2023051807, WO2023051716, WO2023278592, WO2022228387, WO2022022664, WO2022000946, WO2022222921, WO2021163530, WO2020122034, WO2020239097, WO2020142583, WO2020156577, WO2020098774, WO20201967 12, WO2019200382, WO2018125961, WO2018205938, WO2018192576, WO2018218025, WO2017032289, WO201717 7838, WO2017029601, WO2017088723, WO2016155655, WO2015154630, WO2013097225, WO2012130166, WO201 1006794, WO2009046205, WO2009063244, WO2008084261, WO2007138351, WO2006110816, WO2005053662, WO2 005012524, CN113698356, CN113603647, CN115073544, CN108938634, CN104887680, CN110343088, CN108976236, and CN107629071, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0144] vi) DNA PK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more DNA-dependent protein kinase (DNA-PK) inhibitors. DNA-dependent protein kinases (DNA-PKs) are serine / threonine protein kinases that play an important role in DNA repair and maintaining genomic stability. In some embodiments, the DNA-PK inhibitors are one or more NU7441, AZD7648, VX-984, M3814, and CC-115. In some embodiments, references to the term DNA-PK inhibitor include any such DNA-PK inhibitor disclosed in any one of the following patent applications: WO2022187965, WO2021197159, WO2021260583, WO2021204111, WO2021104277, WO2021098813, WO2021022078, WO2020259613, WO2019143678, WO2019143 675, WO2019201283, WO2015058031, WO2014159690, WO2012028233, WO2009010761, WO2006032869, WO2006109084, CN112574179, CN112300132, and CN112300126, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0145] g) Cell cycle inhibitors The compositions and methods described herein may include RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more cell cycle inhibitors. Cell cycle inhibitors target specific proteins involved in regulating the cell cycle, the process by which cells divide and replicate their DNA. Non-limiting examples include cyclin-dependent kinases (CDKs), aurora kinases, and polo-like kinases (PLKs). CDKs are a family of kinases involved in regulating the cell cycle. CDK inhibitors block the activity of these kinases, resulting in cell cycle arrest and / or apoptosis. Aurora kinases are a family of serine / threonine kinases that play a crucial role in regulating mitosis. Aurora kinase inhibitors block the activity of these kinases, resulting in mitotic arrest and cell death. PLKs are a family of serine / threonine kinases involved in regulating multiple stages of the cell cycle. PLK inhibitors block the activity of these kinases, resulting in cell cycle arrest and / or apoptosis.

[0146] i) CDK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more CDK inhibitors. The CDK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. Cyclin-dependent kinases are a family of protein kinases that regulate cell division and proliferation. Cell cycle progression is controlled by cyclins such as CDK1, CDK2, CDK3, CDK4, and CDK6 and their associated cyclin-dependent kinases, although other CDKs such as CDK7, CDK8, and CDK9 are important for transcription. CDK binding to cyclins forms heterodimer complexes that phosphorylate their substrates on serine and threonine residues, which then initiate the events necessary for cell cycle transcription and progression. In some embodiments, the CDK inhibitor is a CDK2 inhibitor. In some embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor. In some embodiments, the CDK inhibitor is a CDK7 inhibitor. In some embodiments, the CDK inhibitor is a CDK9 inhibitor. In some embodiments, the CDK inhibitor is one or more palbociclib, ribociclib, abemaciclib, and trilaciclib. In some embodiments, the CDK inhibitor is one or more of tagtocilib (PF-07104091), sericiclib, borcilib P1446A-05, BLU-222, dynacilib, AT-7519, RGB286638, and AZD4573.

[0147] In some embodiments, references to the term CDK inhibitor include any such CDK inhibitor disclosed in any one of the following patent applications: WO2022166793, WO2022187611, WO2022130304, WO2021227906, WO2021057867, WO2020207260, WO2020138370, WO2020125513, WO2020148635, WO2020215156, WO2020052627, WO2017177837, WO2017162215, WO2017177836, WO2016193939, WO2016 014904, WO2016015598, WO2016015605, WO2015181737, WO2012061156A1, WO2012038411, WO2010020675, WO2010125004, WO2007139732, WO2006024945, CN114478529, CN108794496, CN105294737, CN107652284, KR20180106188, and US2017152269, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0148] ii) Aurora kinase inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more aurora kinase inhibitors. The aurora kinase inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. Aurora kinases are a family of serine / threonine kinases that play a vital role in regulating cell division and maintaining genomic stability. The aurora kinase family consists of three members: aurora A, aurora B, and aurora C. In some embodiments, the aurora kinase inhibitor is one or more palbociclib, ribociclib, and abemaciclib. In some embodiments, the aurora kinase inhibitor is one or more of aricertib, danucertib, valacertib, and MLN8237. In some embodiments, references to the term aurora kinase inhibitor include any such aurora kinase inhibitor disclosed in any one of the following patent applications: WO2021110009, WO2021008338, WO2020112514, WO2019129234, WO2016077161, WO2013143466, WO2011103089, WO2010081881, WO2010133794 WO2009134658, WO2008001886, WO2007095124, WO2007003596, WO2006129064, CN114276227, CN108078991, CN106543155, CN104211692, and CN104098551, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0149] iii) PLK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more polo-like kinase (PLK) inhibitors. The PLK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. PLK is a family of serine / threonine kinases that play a crucial role in regulating cell division, DNA damage response, and mitotic progression, and consists of four members: PLK1, PLK2, PLK3, and PLK4. In some embodiments, the PLK inhibitor is one or more of volasertib, onvansertib, BI2536, and GSK461364. In some embodiments, references to the term PLK inhibitor include any such PLK inhibitor disclosed in any one of the following patent applications: WO2011012534A1, WO2010065134, WO2009130453, WO2009042806, WO2004043936, WO2007030361, WO2006021547, CN115804777, and EP2325185, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0150] iv) Kinesin superfamily inhibitors of microtubule motor proteins In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more kinesin spindle protein (KSP) inhibitors. In some embodiments, the compositions described herein may include one or more kinesin family (KIF) inhibitors. In some embodiments, the KSP inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. KSPs and KIFs are subsets of the kinesin superfamily of microtubule motor proteins. KSPs, also known as Eg5, are members of the kinesin superfamily of motor proteins that play a crucial role in mitotic spindle formation and cell division. KSP inhibitors selectively target rapidly dividing cancer cells by disrupting spindle formation and inducing mitotic arrest. In some embodiments, the KSP inhibitor is one or more of SB743921, monatrol, S-trityl-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 kinesin superfamily inhibitors include any such microtubule motor protein kinesin superfamily inhibitors disclosed in any one of the following patent applications: WO2015114854, WO2015114855, WO2010084186, WO2006101761, WO2006110390, WO2006044825, WO2006078574, WO2005060654, WO2004092147, WO20 04037171, WO2004058700, WO2003050064, WO2003105855, WO2022037665, WO2018114804, WO2017162663, WO2016207089, WO2012073375, JP2014162787, JP2019189590, JP2013166713, and KR20220145566, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0151] v) DYRK1 inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more bispecific tyrosine phosphorylation-regulated kinase 1 (DYRK1) inhibitors. The DYRK1 inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. DYRK1 is a member of the DYRK (bispecific tyrosine phosphorylation-regulated kinase) family of protein kinases. It plays an essential role in various cellular processes, including cell cycle regulation, neuronal development, and transcriptional regulation. In some embodiments, the DYRK1 inhibitor is one or more of harmine, INDY, D4476, and AZ191. In some embodiments, references to the term DYRK1 inhibitor include any such DYRK1 inhibitor disclosed in any one of the following patent applications: WO2023277331A1, WO2023140846A1, WO2017181087A1, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0152] h) Anti-apoptotic protein inhibitors The compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more anti-apoptotic protein inhibitors. In some embodiments, the anti-apoptotic protein inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. Anti-apoptotic inhibitors target proteins that play a role in blocking apoptosis, a form of programmed cell death. Apoptosis is a key mechanism for eliminating damaged or unwanted cells. Anti-apoptotic proteins are a family of proteins that inhibit the apoptotic pathway and thereby prevent cell death. There are several known classes of anti-apoptotic inhibitors, including Bcl-2 inhibitors, XIAP inhibitors, survivin inhibitors, Mcl-1 inhibitors, and FLIP inhibitors. These inhibitors act by binding to specific anti-apoptotic proteins and inhibiting their activity, thereby promoting cell death in cancer cells. In some embodiments, the compositions described herein may include one or more anti-apoptotic protein inhibitors. Anti-apoptotic protein inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the anti-apoptotic protein inhibitors include MCL-1 inhibitors. Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the major anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression, as well as resistance to targeted therapies, including BCL-2 inhibitors such as ABT-263, as well as to conventional chemotherapy. In some embodiments, the anti-apoptotic protein inhibitors include BCL protein inhibitors. Examples of BCL protein inhibitors include, but are not limited to, venetoclax (Veneclexta), navitoclax (ABT-263), A-1331852, S63845, and AT-101.

[0153] i) Autophagy inhibitors The compositions and methods described herein may include RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more autophagy inhibitors. In some embodiments, the autophagy inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil®), spautin-1, SAR405, bafilomycin A1, 5-amino-4-imidazole carboxamidriboside (AICAR), okadaic acid, autophagy-suppressing algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNAs that inhibit the expression of proteins including but not limited to ATG5 (which is involved in autophagy) may also be used. In some embodiments, one or more additional therapies include autophagy inhibitors.

[0154] a) ULK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more Unc-51-like kinase (ULK) inhibitors. The ULK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the ULK inhibitor is a ULK1 / 2 inhibitor. In some embodiments, the ULK inhibitor is one or more of ULK-101, MRT68921, SBI-0206965, MRT67307, MRT68920, MRT68922, MRT199665, LY3009120, and dolsomorphine.

[0155] b) VPS inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more vacuolar protein sorting protein (VPS) inhibitors. The VPS inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. VPS (proteins) are a family of proteins that play a crucial role in the autophagy process by regulating the formation and function of autophagosomes, which are structures that entangle cellular elements and transport them to lysosomes for degradation. Dysregulation of VPS proteins is associated with a variety of diseases, including cancer, neurodegenerative diseases, and infections. In some embodiments, the VPS inhibitor is a VPS34 inhibitor. In some embodiments, the VPS inhibitor is one or more of PIK-III, VPS34-IN1, SAR405, Spautin-1, and NSC185058.

[0156] c) Macropinocytosis inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more macropinocytosis inhibitors. The macropinocytosis inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. A macropinocytosis inhibitor is a compound that can block or reduce the process of macropinocytosis. In some embodiments, the macropinocytosis inhibitor is one or more of EIPA (ethyl isopropyl amiloride), wartmannin, amiloride, apirimod, Dyngo-4a, and latruncrin B.

[0157] j) WNT / β-catenin pathway inhibitors The compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more WNT / beta-catenin pathway inhibitors. In some embodiments, the WNT / beta-catenin pathway inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. The WNT / beta-catenin pathway is a critical signaling pathway that plays a vital role in development, tissue homeostasis, and disease. Dysregulation of this pathway is involved in various cancers and has become an attractive target for cancer treatment. WNT / beta-catenin pathway inhibitors target various components of the pathway, including WNT ligands, receptors, and downstream effectors.

[0158] i) β-catenin inhibitors In some embodiments, the compositions and methods described herein may comprise one or more β-catenin inhibitors. The β-catenin inhibitors may be administered or formulated in combination with the RAS inhibitors described herein and / or any additional therapeutic agents. Beta-catenin is a protein that plays a crucial role in the WNT signaling pathway, which regulates various cellular processes, including cell proliferation, differentiation, and migration. In normal cells, β-catenin levels are tightly regulated by a disruption complex that marks β-catenin for degradation. However, in many cancer cells, the disruption complex is impaired, leading to the accumulation of β-catenin in the nucleus and the activation of target genes involved in tumor growth and metastasis.In some embodiments, the WNT / β-catenin inhibitors are FOG-001, OMP-131R10, Foxy-5, LGK974, RXC004, ETC-159, OMP-54F28, niclosamide, OMP-18R5, OTSA-101, BNC101, DKN-01, sulindac, pyrvinium, E7449, BC2059, PRI-724, SM08502, IWP1, IWP2, IWP3, IWP4, IWP12, 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, Sarinomycin, BMD4702, 3289-8625, J01-017a, FJ9, KY-02061, KY-02327, NSC668036, Petido Pen-N3, SSTC3, CCT031374, TCS 183, XAV939, AZ1366, G007-LK, MSC2504877, G244-LM, IWR-1, JW74, JW55, K-756, NVP-TNKS656, MN-64, R K-287107, WIKI4, KY1220, KYA1797K, MSAB, PKF115-584, CGP049090, AV-65, PNU-74654, Windolfen, IQ-1 One or more of the following: tegavivant, fossenvivant, PNPB-29, ZW4864, SAH-BCL9, carnosic acid, xStAx-VHL, NRX-252114, septuximab vedotin, PF-06647020, LGR5-mc-vc-PAB-MMAE, LGR5-NMS818, CWP232291, PRI-724 (also known as ICG-001), C-82, and BC2059. In some embodiments, references to the term β-catenin inhibitor include any such β-catenin inhibitor disclosed in any one of the following patent applications: CN104388427 and CN103830211, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0159] ii) PORCN inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more porcupine (PORCN) inhibitors. The PORCN inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. PORCN is a membrane-bound O-acyltransferase enzyme that plays a crucial role in the WNT signaling pathway by mediating the palmitoylation of WNT ligands. This palmitoylation is essential for the secretion and signaling activity of WNT proteins. Inhibition of PORCN results in a reduction of WNT signaling activity. In some embodiments, the PORCN inhibitor is one or more of LGK974 (WNT974), ETC-1922159, CGX1321, and CWP232291.

[0160] iii) GSK3 inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more glycogen synthase kinase (GSK3) inhibitors. The GSK3 inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. The GSK3 family consists of two closely related serine / threonine kinases: GSK3α and GSK3β. These kinases are involved in numerous cellular processes, including glycogen metabolism, cell cycle regulation, and Wnt signaling. GSK inhibitors have been studied as potential therapeutic agents for a variety of diseases, including cancer, diabetes, Alzheimer's disease, and bipolar disorder. In some embodiments, the GSK3 inhibitor is one or more of tidoglucib, radubiglucib, LiCl (lithium chloride), CHIR99021, SB216763, AZD1080, and LY2090314. In some embodiments, references to the term GSK3 inhibitor include any such GSK3 inhibitor disclosed in any one of the following patent applications: WO2017153834, WO2014059383, WO2010012398, WO2009017455, WO2003037891, CN107151235, and CN102258783, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0161] iv) CLK inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more Cdc2-like kinase (CLK) inhibitors. The CLK inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. LK (Cdc2-like kinases) is a family of serine / threonine kinases that play a crucial role in regulating premRNA splicing, particularly alternative splicing. There are four members of the CLK family: CLK1, CLK2, CLK3, and CLK4. The CLK family of kinases has been shown to be involved in several diseases, including cancer, neurodegenerative diseases, and viral infections. In some embodiments, the CLK inhibitor is a CLK2 inhibitor. In some embodiments, the CLK2 inhibitor is one or more of lorecivivint, SM08502, SM04690, TG003, KH-CB19, Cmpd-1, T3.5, and CX-4945. In some embodiments, references to the term CLK inhibitor include any such CLK inhibitor disclosed in WO2020006115, which includes the compound structures disclosed in that document, which are specifically incorporated herein by reference.

[0162] k) JAK / STAT pathway inhibitors The compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more JAK / STAT pathway inhibitors. In some embodiments, the JAK / STAT pathway inhibitor may be administered or formulated in combination with the RAS inhibitors described herein and / or any additional therapeutic agents. The Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway is a signaling pathway involved in many cellular processes, including immune responses, cell proliferation, and differentiation. Dysregulation of this pathway is associated with a variety of diseases, including inflammatory disorders, cancer, and autoimmune diseases. Inhibitors of the JAK / STAT pathway can be used to treat these diseases. In some embodiments, the JAK / STAT pathway inhibitor is an inhibitor of JAK1, JAK2, and / or JAK3. In some embodiments, the JAK inhibitor is one or more of the following: ruxolitinib (Jakafi®), pacritinib, fedratinib, tofacitinib (Xeljanz®), abrocitinib, filgotinib, oclacitinib, peficitinib, upadacitinib, deuclavacitinib, delgocitinib, and baricitinib (Olumiant®).In some embodiments, references to the term JAK inhibitor include any such JAK inhibitor disclosed in any one of the following patent applications: WO2023011301, WO2023201044, WO2022143629, WO2022251434, WO2022067106, WO2022033551, WO2021244323, WO2021238817, WO2021238818, WO2021178991, WO2021136345, WO2021190647, WO2020219639, WO2020182 159, WO2020155931, WO2020038457, WO2020219524, WO2020173400, WO2018204233, WO2018204238, WO2018169875, WO2018117152, WO2017215630, WO2016070697, WO2016027195, CN117815195, CN117815367, and CN115969796, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0163] In some embodiments, the JAK / STAT inhibitor is a STAT inhibitor. In some embodiments, the STAT inhibitor is an inhibitor of STAT3 and / or STAT5. In some embodiments, the STAT inhibitor is a STAT3 degrader. In some embodiments, the STAT inhibitor is one or more of TTI-101, C-188-9, WP1066, VVD-130850, LLL12B, STA-21, SD-36, Stattic, S3I-201, OPB-31121, or napabucasin (BBI608). In some embodiments, references to the term STAT inhibitor include any such STAT inhibitor disclosed in any one of the following patent applications: WO2024030628, WO2023164680, WO2023192960, WO2023133336, WO2020206424, WO2023107706, WO2021150543, WO2008151037, and CN109288845, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0164] l) Epigenetic modifiers The compositions and methods described herein may include RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more epigenetic modulators. Epigenetic modulators are a class of therapeutic agents that target enzymes that modify the structure and function of chromatin, the complex of DNA and proteins that make up chromosomes. These enzymes, including histone deacetylases (HDACs), histone methyltransferases (HMTs), and DNA methyltransferases (DNMTs), play a crucial role in gene expression and regulation by modifying DNA packaging and influencing how DNA is read and transcribed. Epigenetic modulators act by altering the activity of these enzymes, either by inhibiting or enhancing their function, in order to regulate gene expression in a specific manner. By targeting specific epigenetic modifications such as acetylation, methylation, and DNA methylation, these therapies have the potential to treat a wide range of diseases, including cancer, inflammatory diseases, and neurological disorders.

[0165] i) HDAC inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more histone deacetylase (HDAC) inhibitors. The HDAC inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. There are several classes of HDACs, including Class I, Class IIa, Class IIb, Class III, and Class IV. Class I HDACs are further divided into HDAC1, HDAC2, HDAC3, and HDAC8, and Class IIa HDACs include HDAC4, HDAC5, HDAC7, and HDAC9. Class IIb HDACs consist of HDAC6 and HDAC10, and Class III HDACs are known as sirtuins. HDAC inhibitors can target various classes of HDACs, and their specific effects on gene expression can vary depending on the HDAC they target. In some embodiments, the HDAC inhibitor is one or more of the following: vorinostat (Zolinza), romidepsin (Istodax), bellinostat (Beleodax), panobinostat (Faridac), entinostat (MS-275), valproic acid (Depakene), trichostatin A (TSA), sodium butyrate, and mosetinostat (MGCD0103). Non-limiting examples of HDAC inhibitors include trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH589, romidepsin, ACY-1215, and panobinostat.In some embodiments, references to the term HDAC inhibitor include any such HDAC inhibitor disclosed in any one of the following patent applications: WO2022110958, WO2021252628, WO2019204550, WO2018178060, WO2016126724, WO2014143666, WO2013041480, and WO2006120456, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0166] ii) BET inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more bromodomain and extraterminal protein (BET) inhibitors. The BET inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. BET (bromodomain and extraterminal) proteins are a family of epigenetic leader proteins that recognize and bind to acetylated lysine residues on histones, resulting in chromatin remodeling and gene expression regulation. Humans have four BET proteins: BRD2, BRD3, BRD4, and BRDT. BET inhibitors specifically target the bromodomain of BET proteins, inhibiting their binding to acetylated lysine residues on histones and resulting in altered gene expression. BET inhibitors are useful in treating cancer and other diseases characterized by dysregulation of gene expression. In some embodiments, the BET inhibitor is one or more of JQ1, I-BET762, OTX015, RVX-208, and CPI-0610. In some embodiments, references to the term BET inhibitor include any such BET inhibitor disclosed in any one of the following patent applications: WO2022046682, WO2022182857, WO2021107657, WO2021107656, WO2020221006, WO2020053660, WO2018097977, WO2017222977, WO2017142881, WO2015075665, WO2015011084, and CN113264930, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0167] iii) EZH2 inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) combined with one or more Zeste homolog enhancer 2 (EZH2) inhibitors. The EZH2 inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. EZH2 is a histone-lysine N-methyltransferase that is a member of the Polycomb repression complex 2 (PRC2) family. EZH2 plays a crucial role in gene expression regulation, particularly by catalyzing histone H3 trimethylation with lysine 27 (H3K27me3), resulting in transcriptional repression of target genes. EZH2 has been found to be overexpressed in several types of cancer and is associated with tumor progression and poor prognosis. In some embodiments, the EZH2 inhibitor is one or more of tazemettostat, GSK2816126, and CPI-1205 (lirametostat). In some embodiments, references to the term EZH2 inhibitor include any such EZH2 inhibitor disclosed in any one of the following patent applications: WO2023030299, WO2022179584, WO2020224607, WO2021243060, WO2021086069, WO2019206155, WO2018133795, WO201 8137639, WO2017184999, WO2017218953, WO2016201328, WO2015195848, WO2013155317, WO2013138361, and CN114621191, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of these documents is incorporated herein by reference.

[0168] iv) Co-REST inhibitors In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more Co-REST inhibitors. The Co-REST inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. Co-REST is a transcriptional co-repressor protein that interacts with various transcription factors to regulate gene expression. Co-REST acts by recruiting histone deacetylase (HDAC) to chromatin, resulting in the repression of gene expression. Inhibition of Co-REST has been proposed as a potential therapeutic strategy for the treatment of various diseases, including neurodegenerative diseases and cancer. In some embodiments, the co-REST inhibitor is one or more of nocodazole, NSC1892, and anacardic acid.

[0169] v) EP300 In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more E1A-binding protein p300 (EP300) inhibitors. The EP300 inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. EP300 is a transcriptional coactivator involved in regulating numerous cellular processes, including chromatin remodeling, DNA damage response, and cell cycle progression. EP300 functions as a histone acetyltransferase, catalyzing the transfer of acetyl groups to lysine residues on histone proteins, resulting in changes in chromatin structure and gene expression. EP300 activity is involved in diseases such as cancer, cardiovascular disease, and neurological disorders. In some embodiments, the EP300 inhibitor is one or more of C646, A-485, NU9056, and L002. In some embodiments, references to the term EP300 inhibitor include any such EP300 inhibitor disclosed in any one of the following patent applications: WO2021213521 and WO2016044694, each of which includes the compound structure disclosed in said document, which is specifically incorporated herein by reference.

[0170] vi)LSD1 In some embodiments, the compositions and methods described herein may include one or more lysine-specific demethylase 1 (LSD1) inhibitors combined with RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805). The LSD1 inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. LSD1 is an enzyme that plays a crucial role in regulating gene expression through histone modification. It specifically removes a methyl group from lysine 4 on histone 3, resulting in gene repression. Dysregulation of LSD1 is associated with a variety of diseases, including cancer and neurodegenerative disorders. In some embodiments, the LSD1 inhibitor is one or more of GSK2879552, IMG-7289, ORY-1001, IMG-8419, SP-2577, CC-90011, HCI-2509, and INCB059872. In some embodiments, references to the term LSD1 inhibitor include any such LSD1 inhibitor disclosed in any one of the following patent applications: WO2021095840, WO2021175079, WO2021058024, WO2020047198, WO2020052649, WO2020015745, WO2020052647, W O2018137644, WO2017184934, WO2017027678, WO2017116558, WO2017149463, WO2016161282, WO2015123465, WO2015123424, WO2013057322, WO2013057320, WO2012135113, CN114805261, CN111072610, CN107174584, CN110478352, CN106432248, and CN106045881, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole of them is incorporated herein by reference.

[0171] vii)PRMT5 In some embodiments, the compositions and methods described herein may include one or more RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more protein arginine methyltransferase 5 (PRMT5) inhibitors. The PRMT5 inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. PRMT5 is a member of the PRMT family that catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the nitrogen atom of an arginine residue in a target protein. PRMT5 is involved in a variety of biological processes, including gene expression regulation, signal transduction, and DNA repair. In some embodiments, the PRMT5 inhibitor is one or more of TNG908, TNG462, AMG193, GSK591, EPZ015666, TC-E5003, and MS023. In some embodiments, references to the term PRMT5 inhibitor include any such PRMT5 inhibitor disclosed in any one of the following patent applications: WO2023001133, WO2022206964, WO2022153161, WO2021068953, WO2021088992, WO2020259478, WO2020205660, WO2020250123, WO2020033288, WO2019102494, WO2019112719, WO2019 180631, WO2018065365, WO2017153186, WO2017212385, WO2017032840, WO2016022605, WO2014100695, WO2014145214, WO2014100719, CN111825656, CN114558014, CN11304554, and CN112778275, each of these, including the compound structures disclosed in the said documents, are specifically incorporated herein by reference, and the whole thereof is incorporated herein by reference.

[0172] viii)MAT2A In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more methionine adenosyltransferase 2A (MAT2A) inhibitors. The MAT2A inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. MAT2A is an enzyme that catalyzes the production of S-adenosylmethionine (SAM), a key cofactor in many biological processes, including DNA methylation, protein methylation, and polyamine synthesis. Elevated MAT2A expression has been associated with various cancers. In some embodiments, the MAT2A inhibitor is one or more of cycloleucine and 2-hydroxy-4-methylthiobutanoic acid. In some embodiments, references to the term MAT2A inhibitor include any such MAT2A inhibitor disclosed in any one of the following patent applications: WO2022256808, WO2022256806, WO2019191470, and CN115716831, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0173] ix) DOT1L In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more telomere silencing disruptor 1-like (DOT1L) inhibitors. The DOT1L inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. DOT1L is a histone methyltransferase enzyme that catalyzes the methylation of lysine 79 on histone H3. This modification is related to transcriptional elongation and is important for maintaining gene expression programs. The DOT1L family includes enzymes involved in epigenetic regulation and transcriptional control, and their dysregulation is associated with a variety of diseases, including cancer. In some embodiments, the DOT1L inhibitor is one or more of EPZ-5676 (pinometostat) and EPZ-004777. In some embodiments, references to the term DOT1L inhibitor include any such DOT1L inhibitor disclosed in any one of the following patent applications: WO2016090271, WO2014100662, and CN108997480, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0174] iix)UBA1 In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more ubiquitin-activating enzyme inhibitors (e.g., UBA1 inhibitors). The UBA1 inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. UBA1, also known as ubiquitin-activating enzyme 1, is a key enzyme involved in the ubiquitination process, a fundamental cellular mechanism for proteolysis and regulation. Ubiquitination involves the covalent binding of ubiquitin molecules to target proteins, their marking for degradation by the proteasome, or the regulation of their activity, localization, or interactions within cells. Several inhibitors have been developed to modulate UBA1 activity with the aim of disrupting ubiquitination-mediated processes in diseased cells. These inhibitors typically include, but are not limited to, adenosine-based inhibitors (e.g., PYR-41 and MLN7243) that compete with ATP for binding to the active site of UBA1, thereby inhibiting ubiquitin activation; covalent inhibitors (e.g., TAK-243 (formerly MLN4924)) that form irreversible bonds with specific amino acid residues of the active site of UBA1, resulting in inhibition of its activity; allosteric inhibitors (e.g., compound 2i) that bind to a site on UBA1 different from the active site and induce conformational changes that inhibit its catalytic activity; and fragment-based inhibitors designed based on smaller molecular fragments that bind to UBA1. In some embodiments, the UBA1 inhibitor is one or more of PYR-41, MLN7243, and TAK-243. In some embodiments, references to the term UBA1 inhibitor include any such UBA1 inhibitor disclosed in any one of the following patent applications: WO2016069393A1, WO2016069392A1, and JP2013237627A2, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0175] m) Additional therapeutic agents useful in combination therapy In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more farnesyltransferase inhibitors. The farnesyltransferase inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. Farnesyltransferase inhibitors (FTIs) are a class of drugs that target the farnesyltransferase enzyme, which plays a role in a process called protein prenylation. Protein prenylation is a critical step in the process of activating certain proteins involved in signaling, cell proliferation, and differentiation. In some embodiments, the farnesyltransferase inhibitor is one or more of tipifarnib, ronafarnib, and lilapradib. In some embodiments, references to the term farnesyltransferase inhibitor include any such farnesyltransferase inhibitor disclosed in any one of the following patent applications: WO2010057028, WO2007042465, WO200136395, WO200064891, WO200042849, WO199938862, WO199928315, WO199829390, WO199426723, CN107312000, CN107365310, KR100375421, KR100388790, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0176] In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more casein kinase inhibitors, in combination with the RAS(ON) inhibitor disclosed herein. In some embodiments, the casein inhibitor is SR-3029, a potent ATP-competitive CK1δ and CK1ε inhibitor.

[0177] In some embodiments, the compositions and methods described herein may include one or more FLT3 inhibitors in combination with the RAS(ON) inhibitors disclosed herein. FLT3 (Fms-like tyrosine kinase 3), also known as CD135, is a receptor tyrosine kinase (RTK) that plays a crucial role in regulating hematopoiesis, the process by which blood cells are formed. It is primarily expressed on hematopoietic stem cells (HSCs) and progenitor cells in the bone marrow and controls cell proliferation, survival, and differentiation. In some embodiments, the FLT3 inhibitors include, but are not limited to, midostaurin, gilteritinib, sorafenib, quizartinib, crenolanib, ponatinib, and quizartinib.

[0178] In some embodiments, the compositions and methods described herein may include one or more RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more TGFβ pathway inhibitors. In some embodiments, the compositions and methods described herein may include one or more TGFβ inhibitors. The TGFβ inhibitors may be administered or formulated in combination with the RAS inhibitor therapies described herein and / or any additional therapeutic agents. TGFβ (transforming growth factor beta) is a multifunctional cytokine involved in a variety of cellular processes, including cell proliferation, differentiation, apoptosis, and immune responses. Dysregulation of the TGFβ signaling pathway is associated with a variety of diseases, including cancer, fibrosis, and autoimmune diseases. In some embodiments, the TGFβ inhibitor is one or more of garnicertiveb (LY2157299) and bactocertiveb (TEW-7197). In some embodiments, the TGFβ inhibitor is one or more of garnicertib, LY2157299, fresolimmab, reldelimab, travedersen, curcumin, resveratrol, and small interfering RNAs (siRNAs) for silencing TGFβ receptor expression. In some embodiments, references to the term TGFβ inhibitor include any such TGFβ inhibitor disclosed in any one of the following patent applications: WO2023043473, WO2020104648, WO2020128850, WO2016140884, WO2007018818, WO2004024159, WO200226935, WO2002062753, WO2002062776, and JP2012087076, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0179] In some embodiments, the compositions and methods described herein may include one or more HSP90 inhibitors combined with RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805). The HSP90 inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. HSP90, also known as heat shock protein 90, is a molecular chaperone that plays a crucial role in regulating the folding, stability, and activity of numerous client proteins involved in various cellular processes, including cell cycle progression, signaling, and apoptosis. In some embodiments, the HSP90 inhibitor is one or more of the following: geldanamycin or its derivatives (e.g., 17-AAG, 17-DMAG), KOS953, radicicol or its derivatives (e.g., PU-H71), SNX-2112, ganetespib, AT13387, onarespib, luminespib, and KW-2478. In some embodiments, references to the term HSP90 inhibitor include any such HSP90 inhibitor disclosed in any one of the following patent applications: WO2021137665, WO2018200534, WO2017151425, WO2015200514, WO2013053833, WO2013009657, WO2013119985, WO2012138894, WO2011044394, WO2009097578, WO2008115719, CN105237533, and CN104030904, each of which includes the compound structure disclosed in the said document, which is specifically incorporated herein by reference.

[0180] In some embodiments, the compositions and methods described herein may include one or more glutathione peroxidase 4 (GPX4) inhibitors combined with RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805). The GPX4 inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. GPX4 is an antioxidant enzyme that plays a crucial role in protecting cells from oxidative stress-induced cell death. GPX4 catalyzes the reduction of lipid hydroperoxides to their corresponding alcohols and functions as a regulator of ferroptosis, a form of regulated cell death driven by lipid peroxideization. In some embodiments, the GPX4 inhibitors are one or more of RSL3, ML162, DPI7, FINO2, MCB-613, CBS9106, ML210, ODSH, and TLN232. In some embodiments, references to the term GPX4 inhibitor include any such GPX4 inhibitor disclosed in any one of the following patent applications: WO2021132592, US2021244715, and KR20220115536, each of which includes the compound structures disclosed in such documents, which are specifically incorporated herein by reference.

[0181] In some embodiments, the compositions and methods described herein may include one or more NRF2 inhibitors combined with RAS(ON) inhibitors (e.g., RMC-6236, RMC-6291, and / or RMC-9805). The NRF2 inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. NRF2 is a transcription factor that modulates the expression of genes involved in cellular antioxidant responses, detoxification, and other cytoprotective pathways. It plays a crucial role in cellular defense mechanisms against oxidative stress and other forms of cellular damage. In some embodiments, the NRF2 inhibitors are one or more of ML385, brusatol, CDDO-Im, RTA-408, and trigonelline. In some embodiments, references to the term NRF2 inhibitor include any such NRF2 inhibitor disclosed in any one of the following patent applications: WO2023051088, WO2021202720, KR2022013610, and CN107519168, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0182] In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more TEA domain (TEAD) inhibitors. The TEAD inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. TEAD is a family of transcription factors that play a crucial role in regulating gene expression during embryonic development and tissue homeostasis. The four members of the TEAD family (TEAD1-4) are transcriptional co-activators that bind to DNA via their conserved TEA domains and interact with other transcription factors to activate the expression of target genes. In some embodiments, the TEAD inhibitor is one or more of VT-107, pan-TEAD, VT-104, verteporfin, CA3, IAG933, K-975, and statins (see, for example, Chapeau, Emilie and Schmelzle, Tobias (2023) IAG933, an oral selective YAP1-TAZ / pan-TEAD protein-protein interaction inhibitor (PPIi) with pre-clinical activity in monotherapy and combinations with MAPK inhibitors. Nature Cancer). In some embodiments, references to the term TEAD inhibitor include any such TEAD inhibitor disclosed in any one of the following patent applications: WO2023280254, WO2023031781, WO2022258040, WO2020070181, WO2018185266, and WO2017064277, each of which includes the compound structures disclosed in the said documents, which are specifically incorporated herein by reference.

[0183] In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more NOTCH / gamma-secretase inhibitors. The NOTCH / gamma-secretase inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the NOTCH / gamma-secretase inhibitor is nilogacestat. In some embodiments, references to the term NOTCH / gamma-secretase inhibitor include any such NOTCH / gamma-secretase inhibitor disclosed in any one of the following patent applications: WO2020208572, WO2017200969, WO2014047390, WO2014047372, WO2011041336, WO2010090954, WO2009008980, WO2009087130, WO2007110335, CN103664904, CN105560244, and KR20200077480, each of which includes the compound structures disclosed in those documents, which are specifically incorporated herein by reference.

[0184] In some embodiments, the compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more hedgehog inhibitors. The hedgehog inhibitor may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. The hedgehog (Hh) family of proteins are secreted signaling molecules that play a vital role in embryonic development and tissue homeostasis in adults. The Hh signaling pathway is involved in regulating cell growth, differentiation, and survival. In some embodiments, the hedgehog inhibitor is one or more of bismodegib (Elivege), sonimodegib (Odomzo), and glassmodegib (Dawlismo). In some embodiments, references to the term hedgehog inhibitor include any such hedgehog inhibitor disclosed in any one of the following patent applications: WO2011063309 and CN107163028, each of which includes the compound structure disclosed in said document, which is specifically incorporated herein by reference.

[0185] The compositions and methods described herein may include a RAS(ON) inhibitor (e.g., RMC-6236, RMC-6291, and / or RMC-9805) in combination with one or more NFκB pathway inhibitors. In some embodiments, the compositions and methods described herein may include one or more NFκB inhibitors. The NFκB inhibitor may be administered or formulated in combination with the RAS inhibitor therapy described herein and / or any additional therapeutic agent. NF-kappa B (NFκB) is a family of transcription factors involved in regulating various cellular processes, including inflammation, immunity, cell survival, and proliferation. Non-limiting examples of NFκB inhibitors include bortezomib (Velcade), curcumin, parthenolide, IKK inhibitors (e.g., IKK-16, BAY11-7082), resveratrol, androgravoliide, and proteasome inhibitors (e.g., MG132, lactacystin).

[0186] In some embodiments, additional therapy involves the administration of side effect limiting agents (e.g., drugs intended to reduce the occurrence or severity of side effects of treatment). For example, in some embodiments, RAS(ON) inhibitors can also be used in combination with therapeutic agents for treating nausea. Examples of drugs that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0187] In some embodiments, one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiotherapy). In some embodiments, one or more additional therapies include therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signaling inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiotherapy) and therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signaling inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors).

[0188] Examples of non-pharmacological treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0189] In some embodiments, RAS(ON) inhibitors may be used as adjuvant therapy after surgery. In some embodiments, RAS(ON) inhibitors may be used as neoadjuvant therapy before surgery.

[0190] Radiotherapy may be used in subjects (e.g., mammals (e.g., humans)) to inhibit abnormal cell proliferation or to treat hyperproliferative disorders such as cancer. Techniques for administering radiotherapy are known in the art. Radiotherapy may be administered via one or a combination of several methods, including, but not limited to, external beam therapy, internal radiation therapy, implanted radiation, stereotactic radiotherapy, total body radiation therapy, radiotherapy, and permanent or temporary intratissue brachytherapy. As used herein, the term “proximity radiation therapy” refers to radiotherapy delivered by spatially confined radioactive material inserted into the body at or near a tumor or other site of proliferative tissue disease. The term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Suitable radiation sources for use as cell conditioners in this disclosure include both solid and liquid forms. In non-limiting examples, the radiation source may be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, or another radionuclide emitting photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material may also be a fluid prepared from any solution of the radionuclide(s), e.g., a solution of I-125 or I-131, or the radioactive fluid may be produced using a suitable fluid slurry containing small particles of a solid radionuclide such as Au-198 or Y-90. Furthermore, the radionuclide(s) may be embodied in gels or radioactive microspheres.

[0191] In some embodiments, RAS(ON) inhibitors can make abnormal cells more sensitive to radiotherapy intended to kill or inhibit the proliferation of such cells. Accordingly, the Disclosure further relates to a method for sensitizing abnormal cells in mammals to radiotherapy, the method comprising administering to a mammal an amount of the compound of the Disclosure that is effective in sensitizing abnormal cells to radiotherapy. The amount of the compound in this method can be determined according to the means for determining an effective amount of such compound described herein. In some embodiments, RAS(ON) inhibitors may be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0192] In some embodiments, the non-pharmacological treatment is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The T cell source is obtained from a subject before T cell proliferation and genetic modification. T cells can be obtained from several sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymic tissue, tissue from infection sites, ascites, pleural fluid, spleen tissue, and tumors. In certain embodiments of this disclosure, any number of T cell lines available in the art may be used. In some embodiments, the T cells are autologous T cells. Regardless of whether the T cells are genetically modified to express a desired protein (e.g., CAR), T cells are generally, for example, U.S. Patent Nos. 6,352,694, 6,534,055, 6,905,680, 6,692,964, 5,858,358, 6,887,466, 6,905,681, and It can be activated and propagated using the methods described in Nos. 7,144,575, 7,067,318, 7,172,869, 7,232,566, 7,175,843, 7,572,631, 5,883,223, 6,905,874, 6,797,514, and 6,867,041.

[0193] In some embodiments, the therapeutic agent for combination therapy may be a steroid. Therefore, in some embodiments, one or more additional therapies include a steroid. Suitable steroids include 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, crocortol, cloprednol, corticosterone, cortisone, cortivazole, deflazacort, desonide, dexoxymethasone, dexamethasone, diflorasone, diflucortol, difprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, flucortin butyl, flucortolone, fluorometholone, fluperolone acetate, flupredniden acetate, fluprednisolone, and flulandrenolide. Examples include, but are not limited to, fluticasone propionate, formocortal, halcinonide, halobetazole propionate, halomethasone, hydrocortisone, loteprednol etavonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, sodium prednisolone phosphate, prednisone, prednival, prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexaacetonide, and their salts or derivatives.

[0194] Further examples of therapeutic agents that may be used in combination therapy with the RAS(ON) inhibitors disclosed herein include compounds described in the following patents: U.S. Patents No. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623, Patent No. 885, and international patent applications Nos. 01 / 37820, 01 / 32651, 02 / 68406, 02 / 66470, 02 / 55501, 04 / 05279, 04 / 07481, 04 / 07458, 04 / 09784, 02 / 59110, 99 / 45009, 00 / 59509, 99 / 61422, 00 / 12089, and 00 / 02871.

[0195] Additional therapeutic agents may be biologics used to treat cancer or related conditions (e.g., cytokines (e.g., interferons or interleukins such as IL-2)). In some embodiments, the biologic is a biologic of the immunoglobulin system, e.g., monoclonal antibodies (e.g., humanized antibodies, fully human antibodies, Fc fusion proteins, or functional fragments thereof) that inflict pain on a target to stimulate an anti-cancer response or antagonize antigens important to cancer. Antibody-drug conjugates are also included.

[0196] The additional therapeutic agent may be an immunomodulator. For example, the additional therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is a drug such as an antibody that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is a drug such as an antibody that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibody, e.g., avelumab, durvalumab, atezolizumab, pizilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or Preusser, M. et al. Checkpoint inhibitors disclosed in al. (2015) Nat. Rev. Neurol. include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirirumab, IPH2101, 1-7F9, and KW-6002. Non-exclusive examples of immunomodulators include the targets specified in Table 1.

[0197] [Table 1-1]

[0198] [Table 1-2]

[0199] Additional therapeutic agents may include anti-TIGIT antibodies such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (ethigirimab).

[0200] Additional therapeutic agents may be drugs that treat cancer or related conditions (e.g., cytotoxic agents, non-peptide small molecules, or other compounds useful in treating cancer or related conditions, collectively referred to as “anticancer agents”). Anticancer agents may be, for example, chemotherapeutic agents or targeted therapy agents.

[0201] Anticancer agents include mitotic inhibitors, insertive antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyrotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracendione-substituted ureas, methylhydrazine derivatives, corticosteroids, progestins, estrogens, antiestrogens, androgens, and gonadotropin-releasing hormone analogs. Further anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, one or more additional therapies comprise two or more anticancer agents. Two or more anticancer drugs can be used in a cocktail, either administered in combination or individually. Preferred administration regimens for combination anticancer drugs are known in the art and are described, for example, in Saltz et al., Proc.Am.Soc.Clin.Oncol.18:233a(1999) and Douillard et al., Lancet 355(9209):1041-1047(2000).

[0202] Other non-exclusive examples of anticancer drugs include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents, e.g., thiotepa and cyclophosphamide; alkyl sulfonates, e.g., busulfan, improsulfan, and pigosulfan; aziridines, e.g., be Nzodopa, carbocone, metsuredopa, and uredopa; ethyleneimines and methylamelamines, e.g., altoretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bratacin and bratacinone); camptothecin (e.g., synthetic analog topotecan); bryostatin; callistatin; CC-1065 (e.g., its adzeresin, karzeresin, and (Bayzeresin synthetic analogs); Cryptophycin (specifically, Cryptophycin 1 and Cryptophycin 8); Dorastatin; Duocalmycin (e.g., synthetic analogs KW-2189 and CB1-TM1); Erytherobin; Pancratistatin; Sarcodictiin A; Spongistin; Nitrogen mustard, e.g., Chlorambucil, Chlornafadin, Colophosphamide, Estramustine, Ifosfamide, Mechloretamine, Mechlor Tamin oxide hydrochloride, melphalan, nobenbitin, fenestrine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas, e.g., camulstine, chlorozotosine, photemustine, lomustine, nimustine, and ranimustine; antibiotics, e.g., engine antibiotics (e.g., calicheamicin, e.g., calicheamicin gamma II and calicheamicin omega II (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins such as dynemicin A; bisphosphonates such as clodronate; esperamicin;Neocardinostatin chromophore and related pigment protein enediin antiobiotic chromophore, acrasinomycin, actinomycin, autoramycin, azaserin, bleomycin, kactinomycin, calicheamicin, carabicin, kaminomycin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyano Morpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potophyllomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zolbicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); denopterin, pteropterin Folic acid analogs such as trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid infusions such as phloric acid; acegraton; Aldophosphamide glycoside; aminolevulinic acid; enyluracil; amsacrine; bestrabusil; bisanthren; edatrexate; defofamine; demecolsin; diaziquan; elfomithine; eriptinium acetate; epotilon B and other epotilons; etogluside; gallium nitrate; hydroxyurea; lentinan; mytansinoids such as ronidynin, mytansin and ansamitosin; mitogluzone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet;Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK (Trademark) Polysaccharide Complex (JHS Natural Products, Eugene, OR); Lazoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic acid; Triadicone; 2,2',2''-Trichlorotriethylamine; Trichothecenes such as T-2 toxin, Veraculine A, Loridine A, and Anguidine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Si Clophosphamide; thiotepa; taxoids, e.g., Taxol® (paclitaxel), Abraxane® (chromophore-free, albumin-modified nanoparticle formulation of paclitaxel), and Taxotere® (doxetaxel); chlorambucil; tamoxifen (Nolvadex®); raloxifene; aromatase-inhibiting 4(5)-imidazole; 4-hydroxytamoxifen; trioxyfen; Keoxyfen; LY117018; Onapristone; Toremifene (Fareston®); Flutamide, Nilutamide, Bicalutamide, Leuprolide, Goserelin; Chlorambucil; Gemzar® Gemcitabine; 6-Thiogunine; Mercaptopurine; Platinum analogs such as cisplatin, oxaliplatin, and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Examples include Navelbine® (vinorelbine); novantron; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicin; capecitabine (e.g., Xeloda®); and any pharmaceutically acceptable salts of the above.

[0203] Non-exclusive examples of additional anticancer drugs include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, Avisin, avagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, and alafara. Zin, Arbocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracendione, Anti-CD22 immunotoxin, Antitumor agents (e.g., cell cycle nonspecific antitumor agents, and other antitumor agents described herein), Antitumor herbs, Apadiquon, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW2992, Bilicodal, Brostarisin, Briostatin, Butionine sulfoximine, CBV (chemotherapy), Ca Licurin, dichloroacetate, discordamorid, erusamitolu, enocitabine, eribulin, exatecan, exislind, ferginol, forodesine, phosfestrol, ICE chemotherapy regimen, IT-101, imexone, imiquimod, indocarbazole, irofluben, lanikidal, lalotaxel, lenalidomide, lucanton, lulutotecan, maphosphamide, mitozolomid, napoxidine, nedaplatin, olaparib, ortataki Examples include cell, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, reximod, rubitecan, SN-38, salinosporamide A, sapacitabine, stanford V, swainsonin, talaporfin, talikidal, tegafur-uracil, temodal, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, bajimezan, vinflunin, ZD6126, and zoskidal.

[0204] Further non-limiting examples of anticancer drugs include vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mitramycin), mitomycin, enzymes (e.g., L-asparaginase, which systemically metabolizes L-asparagine and deprives cells of the ability to synthesize their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., mechloretamine, cyclophosphamide and its analogs, melphalan, and chlorambucil), ethyleneimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), alkyl sulfonates (e.g., busulfan), and nitrosulfonates. Antiproliferative / antimitotic metabolites and related inhibitors such as raea (e.g., carmustine (BCNU) and its analogues, as well as streptozocin), trazeneth-dacarbadinine (DTIC), folate analogues, pyrimidine analogues (e.g., fluorouracil, phloxuridine, and cytarabine), purine analogues, and mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), and aromatase inhibitors (e.g., anastrozosine). PI3K inhibitors such as PI3K delta-agonists (e.g., exemestane and letrozole), platinum-coordinate complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, DNA binders (e.g., Zalypsis®), PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib;Multi-kinase inhibitors (e.g., TG02 and sorafenib), hormone agonists such as hormones (e.g., estrogen) and leutinizing 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., GRN163L), cell surface monoclonal antibodies (e.g., Examples include natural products such as anti-CD38 (HUMAX-CD38), anti-CSl (e.g., elotuzumab), P13K / Akt inhibitors (e.g., perifosine), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zanestra®), anti-CD138 (e.g., BT062), Torcl / 2-specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), and cFMS inhibitors (e.g., ARRY-382).

[0205] In some embodiments, the anticancer agent is selected from mechloretamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any of the aforementioned analogues or derivative variants. In some embodiments, the anticancer agent is JAB-3312.

[0206] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist. In some embodiments, additional therapeutic agents include immunomodulatory therapies such as ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immune checkpoint inhibitors. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor such as afatinib.

[0207] In some embodiments, additional therapeutic agents are selected from the group consisting of MEK inhibitors, HER2 inhibitors, SHP2 inhibitors, CDK4 / 6 inhibitors, mTOR inhibitors, SOS1 inhibitors, and PD-L1 inhibitors. See, for example, Hallin et al., Cancer Discovery, DOI:10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575:217 (2019). In some embodiments, the RAS(ON) inhibitors of this disclosure are used in combination with MEK inhibitors and SOS1 inhibitors. In some embodiments, the RAS(ON) inhibitors of this disclosure are used in combination with PD-L1 inhibitors and SOS1 inhibitors. In some embodiments, the RAS(ON) inhibitors of this disclosure are used in combination with PD-L1 inhibitors and SHP2 inhibitors. In some embodiments, the RAS(ON) inhibitors of the Disclosure are used in combination with MEK inhibitors and SHP2 inhibitors. In some embodiments, the cancer is colorectal cancer, and the treatment comprises administering the Ras inhibitor of the Disclosure in combination with a second or third therapeutic agent.

[0208] Examples of proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0209] Immunotherapy includes, but is not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically modified T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1, anti-PD-L1, anti-CTLA4, anti-LAGl, and anti-OX40 agents.

[0210] Immunomodulators (IMiDs) are a class of immunomodulatory drugs (drugs that modulate the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0211] Exemplary anti-PD-1 antibodies and their uses are described in Goldberg et al., Blood 2007, 110(1):186-192, Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761, and WO06 / 121168A1), and are described elsewhere in this specification.

[0212] GITR agonists include GITR fusion proteins described in U.S. Patent Nos. 6,111,090, 8,586,023, WO2010 / 003118, and WO2011 / 090754, or, for example, U.S. Patent Nos. 7,025,962, EP1947183, 7,812,135, 8,388,967, 8,591,886, 7,618,632, EP1866339, and WO201 This includes, but is not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the anti-GITR antibodies described in 1 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0213] Another example of a therapeutic agent that may be used in combination with RAS(ON) inhibitors is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions, antibodies, antigen-binding domains, radionuclides, and combinations and conjugates thereof, which are synthetically prepared in vitro. Anti-angiogenic agents may be agonists, antagonists, allosteric modulators, toxins, or, more generally, may act to inhibit or stimulate their targets (e.g., by activating or inhibiting receptors or enzymes), thereby promoting cell death or halting cell proliferation. In some embodiments, one or more additional therapies include an anti-angiogenic agent.

[0214] Anti-angiogenic agents can be MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-specific examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include arecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors include WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, and WO99 / 528. As described in 89, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085, and U.S. Patents 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those with little or no activity to inhibit MMP-1. More preferred are those that selectively inhibit MMP-2 or AMP-9 compared to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO32-3555, and RS13-0830.

[0215] Further exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to kinase domain receptors), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind to them or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712, US6,413,932), anti-Tweak agents (e.g., antibodies or antigen-binding domains that specifically bind, or soluble Tweak receptor antagonists; see US6,727,225), ADAM distointegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), and anti-eph receptors or anti-ephrin antibodies or antigen-binding domains that specifically bind. Examples include regions (U.S. Patents No. 5,981,245, No. 5,728,813, No. 5,969,110, No. 6,596,852, No. 6,232,447, No. 6,057,124, and their patent family members), anti-PDGF-BB antagonists (e.g., antibody or antigen-binding regions that specifically bind to them), antibody or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibody or antigen-binding regions that specifically bind to them). Additional anti-angiogenic agents include SD-7784 (Pfizer, USA); sirengitide (Merck KGaA, Germany, EPO0770622); pegaptanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, US5712291); ilomastat (Arriva, USA, US5892112); emaxanib (Pfizer, USA, US5792783); and batalanib (Novartis, Switzerland).2-Methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); Anecoltabuacetate (Alcon, USA); Alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands), DAC anti-angiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); Fibrinogen-E fragment (BioActa, UK); Angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); Maspin (Sosei, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP02233610); Platelet factor IV (RepliGen, USA, EP407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL784 (Exelixis, USA); XL647 (Exelixis, USA); MAb, alpha-5 beta-3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, USA); Enzastaurin hydrochloride (Lilly, USA); CEP7055 (Cephalon, USA and Sanofi-Synthelabo, France);BC1 (Genoa Institute of Cancer Research, Italy); rBPI21 and BPI-derived anti-angiogenic drugs (XOMA, USA); PI88 (Progen, Australia); Silengitide (Merck KGaA, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN161 (Attenuon, USA); 2-Methoxyestradiol (Boston Children's Hospital, USA); ZD6474 (AstraZeneca, UK); ZD6126 (Angiogene Pharmaceuticals, UK); PPI2458, (Praecis, USA); AZD9935, (AstraZeneca, UK); AZD2171, (AstraZeneca, UK); batalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitor, (EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA); xantollysole, (Yonsei University, South Korea); vaccine, gene-based, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX103, (University of California at San Diego, USA); PX478, (ProlX, USA); metastatin, (EntreMed, USA); troponin I, (Harvard University, USA); SU6668, (SUGEN, USA); OXI4503, (OXiGENE, USA); o-Guanidine, (Dimensional Pharmaceuticals, USA);Motupolamine C (British Columbia University, Canada); CDP791 (Celltech Group, UK); Atiprimod (pINN) (GlaxoSmithKline, UK); E7820 (Eisai, Japan); CYC381 (Harvard University, USA); AE941 (Aeterna, Canada); Vaccine, Angiogenesis (EntreMed, USA); Urokinase Plasminogen Activator Inhibitor (Dendreon, USA); Ogluphanide (pINN) (Melmotte, USA); HIF-1 Alpha Inhibitor (Xenova, UK); CEP5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR31372 (Korea Research Institute of Chemical Technology, South Korea); GW2286, (GlaxoSmithKline, UK); EHT0101, (ExonHit, France); CP868596, (Pfizer, USA); CP564959, (OSI, USA); CP547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN633, (Kirin Brewery, Japan); Drug delivery system, intraocular, 2-methoxyestradiol; Anguinex (Maastricht University, Netherlands, and Minnesota University, USA); ABT510 (Abbott, USA); AAL993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-alpha inhibitor; SU11248 (Pfizer, USA and SUGEN USA); AB T518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA);MAb, alpha-5 beta (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK, and Johnson & Johnson, USA); GFB116 (South Florida University, USA and Yale University, USA); CS706 (Sankyo, Japan); Combrestatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES2690 (Bayer, Germany); AGM1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA); CV247 (Ivy Medical, UK); CKD732 (Chong Kun Dang, South Korea); Ilsogladine, (Nippon Shinyaku, Japan); RG13577 (Aventis, France); WX360 (Wilex, Germany); Squalamine (Genaera, USA); RPI4610 (Sirna, USA); Heparanase inhibitor (InSight, Israel); KL3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK229561 (Novartis, Switzerland, and Schering AG, Germany); XMP300 (XOMA, USA); VGA1102 (Taisho, Japan); VE-Cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA);TZ93(Tsumura,Japan);TumStatin(Beth Israel Hospital,USA);This includes cleaved soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0216] Further examples of therapeutic agents that may be used in combination with the RAS(ON) inhibitors disclosed herein include agents (e.g., antibodies, antigen-binding domains, or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), as well as antibodies or antigen-binding domains that specifically bind to the receptor c-Met.

[0217] Another example of therapeutic agents that can be used in combination with RAS(ON) inhibitors is antineoplastic agents. In some embodiments, one or more additional therapies include antineoplastic agents. Non-limiting examples of antineoplastic agents include acemannan, acralubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostin, aminolevulinic acid, amrubicin, amsacrin, anagrelide, anastrozole, ancer, ancestim, algravin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, bromodeoxyuridine, capecitabine, cermoloukin, cetrorelix, cladribine, clotrimazole, and sita. Rabinocophage, DA3030 (Dong-A), daclizumab, deniroukin difutitox, deslorerin, dexrazoxane, dilazep, docetaxel, docosanol, doxelcalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, ederfosine, edrecolomab, eflornithine, emiteflu, epirubicin, epoeth Interferon alpha, etoposide phosphate, exemestane, exislind, fadrozol, filgrastim, finasteride, fludarabine phosphate, formestan, hotemustine, gallium nitrate, gemcitabine, gemtuzumabuzogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin (imiquimod, interferon alpha, interferon alpha, natural type) Interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-NI, interferon alpha-n3, interferon alphacon-1, interferon alpha, natural type, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural type interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguan, irinotecan,Ilsogladine, Lanreotide, LC9018 (Yakult), Leflunomide, Lenograstim, Lentinan sulfate, Letrozole, Leukocyte alpha interferon, Leuprorelin, Levamisole + Fluorouracil, Rialozol, Lovaplatin, Ronidamin, Lovastatin, Masopropyl, Melalsoprole, Metoclopramide, Mifepristone, Miltefosine, Millimostim, Mispaired double-stranded RNA, Mitoguazone, Mitractol, Mitoxantrone, Morglamostim, Nafarelin, Naloxone + Pentazocine, Naltogra Stim, Nedaplatin, Niltamide, Noscapine, Novel Erythropoiesis-Promoting Protein, NSC631570 Octreotide, Oprelbequin, Osateron, Oxaliplatin, Paclitaxel, Pamidronic Acid, Pegaspargase, Peginterferon Alpha-2b, Pentosan, Sodium Polysulfate, Pentostatin, Picibanil, Pirarubicin, Rabbit Antithymocyte Polyclonal Antibody, Polyethylene Glycol Interferon Alpha-2a, Porfimer Sodium, Raloxifene, Larcitrexed, Rasbrien Bodyment (r Asburiembodiment, etidronate rhenium Re186, RII retinamide, rituximab, romultide, samarium (153Sm) lexidonam, salglamostim, schizophyllan, sobuzoxane, sonelmin, strontium-89 chloride, suramin, tasonelmin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfacin, thyroid-stimulating hormone alpha, topotecan, toremifene, tositumomab-iodine-131, trastuzumab, treosulfa N, tretinoin, trilostane, trimethrexate, triptorelin, tumor necrosis factor alpha, natural type, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma solubilizing solution vaccine, barrubicin, verteporfin, vinorelbine, bilirulysine, dinostatin stimulamer or zoledronic acid; Abarelix; AE941 (Aeterna), ambamustin, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), decitabine, dexaaminoglutethimide, diazicon, EL532 (Elan),EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, gallocitabine, gastrin-17 immunogene, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxyfen, LDI200 (Milkhaus), religistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine-131 MAb (Techni clone), polymorphoemic mucin-yttrium 90 MAb (Antisoma), marimast, menogalil, mitumomab, motexafine, gadolinium, MX6 (Galderma), nelarabine, noratexed, P30 protein, pegvisomant, pemetrexed, porphyromycin, prinomast, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparphosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, saliblastin, thrombopoietin, tin ethylethiopurine, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysis product vaccine (New York Medical College), viral melanoma cell solubilized vaccine (Royal Examples include Newcastle Hospital, or Valspodal.

[0218] Additional examples of therapeutic agents that can be used in combination with RAS(ON) inhibitors include ipilimumab (Yervoy®), tremelimumab, galiximab also known as BMS-936558, nivolumab (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, Atasicept, CP-870893, Lucatumumab, Dasetuzumab, Muromonab-CD3, Ipilumumab, MEDI4736 (Imfinzi®), MSB0010718C, AMP224, Adalimumab (Humira®), Ad-Trastuzumab Emtansine (Kadcyla®), Aflibercept (Eylea®), Alemtuzumab (Campath®), Basiliximab (Simulect®), Belimumab ( Benlysta®, basiliximab (Simulect®), belimumab (Benlysta®), brentuximab vedotin (Adcetris®), canakinumab (Ilaris®), certolizumab pegol (Cimzia®), daclizumab (Zenapax®), daratumumab (Darzalex®), denosumab (Prolia®), eculizumab (Soliris®), efalizumab (Raptiva®) ), gemtuzumab ozogamicin (Mylotarg®), golimumab (Simponi®), ibritumomab tiuxetan (Zevalin®), infliximab (Remicade®), motabizumab (Numax®), natalizumab (Tysabri®), obinutuzumab (Gazyva®), ofatumumab (Arzerra®), omalizumab (Xolair®), palivizumab (Synagis®), pertuzumab Examples include mab (Perjeta®), pertuzumab (Perjeta®), ranibizumab (Lucentis®), laxibakumab (Abthrax®), tocilizumab (Actemra®), tositumomab, tositumomab-i-131, tositumomab and tositumomab-i-131 (Bexxar®), ustekinumab (Stelara®), AMG102, AMG386, AMG479, AMG655, AMG706, AMG745, and AMG951.

[0219] This disclosure provides a pharmaceutical composition comprising, as an activator, one or more RAS(ON) inhibitors or pharmaceutically acceptable salts thereof in combination with one or more therapeutic agents disclosed herein, and a pharmaceutically acceptable excipient.

[0220] In some embodiments, the active ingredient in the pharmaceutical composition is a unit dose appropriate for administration in a therapeutic regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for oral administration, e.g., oral tablets (aqueous or nonaqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those targeted for intracellular absorption, boluses, powders, granules, and pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as sterile solutions or suspensions, or as sustained-release formulations; topical application, e.g., as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or oral cavity; vaginal or rectal administration, e.g., as pessaries, creams, or foams; sublingual administration; intraocular administration; transdermal administration; or administration via nasal, intrapulmonary, and other mucosal surfaces.

[0221] The combination therapies described herein, whether expressly stated or not, may be provided or used in salt form, for example, pharmaceutically acceptable salt form, unless expressly stated otherwise.

[0222] RAS(ON) inhibitors may have ionic groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts with inorganic or organic acids, or, in the case of the acidic form of the RAS(ON) inhibitor, the salts may be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art for forming acid addition salts, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid, and for forming basic salts, such as potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, and various amines. Methods for preparing suitable salts are well established in the art.

[0223] Typical acid addition salts include acetate, adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and 2-(optionally substituted) hydroxyethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, toluenesulfons, undecanoic acid, and valersates. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and amine cations, including but not limited to non-toxic ammonium, quaternary ammonium, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0224] For use as a treatment for a subject, a RAS(ON) inhibitor, or a pharmaceutically acceptable salt thereof, can be formulated as a pharmaceutical or veterinary composition. Depending on the subject to be treated, the method of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy, the compound, or a pharmaceutically acceptable salt thereof, is formulated in a manner consistent with these parameters. A summary of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988 - 1999, Marcel Dekker, New York, each of which is incorporated herein by reference in its entirety.

[0225] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% (weight % or volume %) of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt thereof, can be present in an amount of up to 95% of the total weight of the composition, such as a pharmaceutical composition.

[0226] The compositions can be provided in dosage forms suitable for intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, dermal, subcutaneous, topical, transdermal, sublingual, nasal, intravaginal, intravesical, intraurethral, intrathecal, epidural, transtympanic, or intravitreal administration, or for injection, inhalation, or direct contact with the nasal, urogenital, reproductive, or oral mucosa. Thus, the pharmaceutical compositions can be, for example, in the form of tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, medicated drinks, osmotic delivery devices, suppositories, enemas, injection solutions, implants, sprays, preparations suitable for iontophoresis delivery, or aerosols. The compositions can be formulated according to conventional pharmaceutical practice.

[0227] The formulations can be prepared by methods suitable for systemic administration, or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection), or can be prepared for transdermal, transmucosal, or oral administration. Formulations generally include a diluent, and in some cases, adjuvants, buffers, preservatives, etc. The compound, or its pharmaceutically acceptable salt, can also be administered in liposomal compositions or as microemulsions.

[0228] For injection, the formulations can be prepared in conventional forms as solutions or suspensions, or as solid forms suitable for solution or suspension in a liquid prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol, etc. Such compositions can also contain certain amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffers such as sodium acetate, sorbitan monolaurate, etc.

[0229] Various drug sustained-release systems have also been devised. See, for example, U.S. Patent No. 5,624,677. Systemic administration can also include relatively non-invasive methods, examples of which include the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present disclosure, or their pharmaceutically acceptable salts. Suitable forms include syrups, capsules, and tablets, as understood in the art.

[0230] Each compound described herein, or its pharmaceutically acceptable salt, can be formulated by various methods known in the art. For example, the first agent and the second agent of a combination therapy can be formulated together or individually. Other modalities of combination therapy are described herein.

[0231] Individually formulated or separately manufactured drugs can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing two pills, pills and powder, suppositories and liquids in vials, two topical creams, etc. Kits may include optional components that facilitate the administration of a unit dose to a target, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. In addition, unit dose kits may include instructions for use for the preparation or administration of the composition. Kits may be manufactured as single-use unit doses for a particular target (where the efficacy of individual compounds or their pharmaceutically acceptable salts changes at a constant concentration or as treatment progresses), as multiple-use doses for a specific target, or kits may contain multiple doses suitable for administration to multiple targets ("bulk packaging"). The components of the kit may be assembled into cartons, blister packs, bottles, tubes, etc.

[0232] Preparations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic, pharmaceutically acceptable excipients. These excipients may include, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starch containing potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulators and disintegrants (e.g., cellulose derivatives containing microcrystalline cellulose, starch containing potato starch, croscarmellose sodium, alginate, or arginine); binders (e.g., sucrose, glucose, sorbitol, acacia, arginine, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, aluminum magnesium silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); as well as smoothers, lubricants, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may include colorants, flavoring agents, plasticizers, wetting agents, and buffering agents.

[0233] Two or more compounds can be mixed or dispensed in a tablet, capsule, or other vehicle. In one example, the first compound is contained inside the tablet and the second compound is on the outside, such that a substantial portion of the second compound is released before the first compound is released.

[0234] Formulations for oral use may be provided as chewable tablets, or as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium (e.g., peanut oil, liquid paraffin, or olive oil). Powders, granules, and pellets may be prepared using the above-mentioned components in conventional methods, such as using a mixer, fluidized bed apparatus, or spray dryer, for example, under tablets and capsules.

[0235] Dissolution or diffusion-controlled release can be achieved by appropriate coatings for tablet, capsule, pellet, or granule formation of the compound, or by incorporating the compound, or a pharmaceutically acceptable salt thereof, into a suitable matrix. Controlled release coatings may include one or more of the above-mentioned coating materials, or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate / butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-(optionally substituted) hydroxyl methacrylate, methacrylate hydrogel, 1,3-butylene glycol, ethylene glycol methacrylate, or polyethylene glycol. In controlled-release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, Carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0236] Liquid forms in which the compounds of this disclosure, or pharmaceutically acceptable salts thereof, and compositions may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0237] In general, when administered to humans, the oral dosage of any of the compounds of this disclosure, or any of its pharmaceutically acceptable salts, depends on the properties of the compound and can be readily determined by those skilled in the art. The dosage may be, for example, about 0.001 mg to about 2000 mg / day, about 1 mg to about 1000 mg / day, about 5 mg to about 500 mg / day, about 100 mg to about 1500 mg / day, about 500 mg to about 1500 mg / day, about 500 mg to about 2000 mg / day, or any range variable therein. In certain embodiments, RMC-6236 may be administered in doses of about 10 mg to 500 mg per day. In certain embodiments, RMC-6236 may be administered in doses of about 200 mg to 400 mg per day. In certain embodiments, RMC-6236 may be administered in doses of about 300 mg per day. In certain embodiments, RMC-6291 may be administered in doses of approximately 50 mg to 800 mg per day. In certain embodiments, RMC-6291 may be administered in doses of approximately 200 mg to 600 mg per day. In certain embodiments, RMC-6291 may be administered in doses of approximately 400 mg per day (e.g., 200 mg twice a day). In certain embodiments, RMC-9805 may be administered in doses of approximately 150 mg to 2000 mg per day. In certain embodiments, RMC-9805 may be administered in doses of approximately 1000 mg to 1400 mg per day.

[0238] In some embodiments, the pharmaceutical composition may further include additional compounds having antiproliferative (e.g., anticancer) activity. Depending on the method of administration, the compounds, or pharmaceutically acceptable salts thereof, are formulated into a suitable composition that allows for easy delivery. Each compound, or pharmaceutically acceptable salt thereof, of the combination therapy may be formulated in various ways known in the art. For example, the first and second agents of the combination therapy may be formulated together or individually. Preferably, the first and second agents are formulated together for simultaneous or near-simultaneous administration of the drugs.

[0239] It will be understood that the compounds and pharmaceutical compositions of this disclosure can be formulated and used in combination therapy, that is, the compounds and pharmaceutical compositions can be formulated or administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures. Specific combinations of therapies (therapeutic agents or procedures) using combination regimens will take into account the suitability of the desired therapeutic agent or procedure and the desired therapeutic effect to be achieved. Furthermore, it will be understood that the therapies used may achieve the desired effect for the same disorder or different effects (e.g., control of any adverse effects).

[0240] In combination therapy, each drug may be administered independently, as described herein, 1 to 4 times daily for 1 to 1 year, and may even be administered for the lifetime of the patient. Chronic long-term administration may be indicated.

[0241] In one embodiment, the disclosure relates to a method for treating a disease or disorder characterized by RAS activity abnormality (e.g., cancer or RAS disease). In some embodiments, the disease or disorder is cancer (e.g., cancer having one or more RAS mutations that cause RAS activity abnormality). A non-limiting example of non-cancerous RAS-related diseases or disorders is shown in Table 2. In each embodiment, the method generally involves administering to a subject a therapeutically effective dose of a RAS(ON) inhibitor in combination with one or more therapeutic agents. Preferred RAS(ON) inhibitors and additional therapeutic agents are described above.

[0242]

Table 2-1

[0243]

Table 2-2

[0244] The present disclosure also provides a method of treating cancer in a subject in need thereof, wherein the cancer comprises a RAS mutation. In one embodiment, the addition of a RAS(ON) inhibitor synergistically increases the activity of one or more additional therapeutic agents. To determine the synergistic effect of the combination, any method for determining whether two or more therapeutic agents, such as the methods described herein, exhibit a synergistic effect may be used.

[0245] Several mathematical models have been developed to determine whether two compounds act synergistically, i.e., beyond a mere additive effect. For example, Loewe additivity (Loewe (1928) Physiol. 27:47-187), Bliss independence (Bliss (1939) Ann. Appl. Biol. 26:585-615), Highest Single Agent, ZIP (Yadav et al (2015) Comput Struct Biotech J 13:504-513), and other models (Chou & Talalay (1984) Adv Enzyme Regul 22:27-55.#6382953, and Greco et al. (1995) Pharmacol Rev 47(2):331-85.#7568331) are models well-known in the pharmaceutical industry and can be used to calculate a "synergy score" indicating whether a synergistic effect has been detected and the magnitude of such a synergistic effect. Additional models for determining the synergistic effect of two compounds can be found in the examples below.

[0246] Generally, mathematical models use data obtained from single drug values ​​to determine the predicted additive effect of a combination and compare it to the observed effect of the combination. If the observed effect is greater than the predicted effect, the combination is considered synergistic. For example, the Bliss independence model compares the observed combination response (Yo) to the predicted combination response (Yp) obtained under the assumption that there is no effect from drug-drug interactions. Typically, if Yo is greater than Yp, the combination effect is considered synergistic.

[0247] In some embodiments, as used herein, “synergistic effect” means a combination of a RAS(ON) inhibitor and one or more additional therapeutic agents, for example, any beneficial or desired outcome including in vitro and clinical outcomes or endpoints described herein, which is greater than the sum of the effects observed when the RAS(ON) inhibitor or the additional therapeutic agent is administered alone.

[0248] RAS(ON) inhibitors and one or more additional therapeutic agents may be administered simultaneously or sequentially. RAS(ON) inhibitors and one or more additional therapeutic agents may be administered as a single formulation or as separate formulations. In some embodiments, the RAS(ON) inhibitor is administered in a first period and one or more additional therapeutic agents are administered in a second period, with the first and second periods not overlapping and the first period preceding the second; or one or more additional therapeutic agents and the RAS(ON) inhibitor are administered in a second period, with the first and second periods not overlapping and the first period preceding the second.

[0249] In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small intestine cancer, ampulla cancer, germ cell carcinoma, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophageal cancer, GI neuroendocrine cancer, ovarian cancer, sex cord-stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal cancer, endometrial cancer, or melanoma. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is pancreatic cancer.

[0250] In some embodiments, combination therapy can be used to treat a wide variety of cancers, including astrocytocyte, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocyte, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. Other cancers include, for example, heart: e.g., sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lung: e.g., bronchogenic carcinomas (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrotoxic hamartoma, mesothelioma; gastrointestinal tract: e.g., esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreatic (tubule) Adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, lipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); urogenital system: e.g., kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (Seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: e.g., liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: e.g., gallbladder cancer, duodenal papilla cancer, cholangiocarcinoma; Bone: e.g., osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, Osteochondroma (osteochondrial exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: e.g., skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, gliomas), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma);Gynecological conditions: For example, the uterus (endometrial cancer, uterine cancer, endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (fetal rhabdomyosarcoma)). ), fallopian tubes (carcinoma); hematological system: e.g., blood (myeloid leukemia (acute and chronic), acute lymphoblastic myeloproliferative neoplasm), multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: e.g., malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: e.g., neuroblastoma.

[0251] In some embodiments, the cancer includes RAS mutations such as the RAS mutations described herein. In some embodiments, the mutations are the following KRAS variants: G12D, G12V, G12C, G13D, G12R, G12A, G12S, A146T, G13C, K117N, A146V, G12F, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof; the following HRAS variants: G13R, G12S, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and the following NRAS variants: G12D, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof; or selected from any combination of the above, in some embodiments the cancer contains a KRAS mutation selected from the group consisting of G12C, G12D, G13C, G12V, G13D, G12R, and G12S. In some embodiments the cancer contains the G12C variant of NRAS. In some embodiments, the cancer contains RAS mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer contains at least two RAS mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V.

[0252] In some embodiments, the compounds of the Disclosure bind to or inhibit two or more RAS variants. In some embodiments, the compounds may inhibit both KRAS G12D and KRAS G12V. In some embodiments, the compounds may bind to or inhibit both KRAS G12V and KRAS G12S. In some embodiments, the compounds of the Disclosure bind to or inhibit wild-type RAS in addition to RAS variants. In some embodiments, the compounds of the Disclosure bind to or inhibit RAsamp (e.g., K-, H-, or NRAsamp and KRAS) in addition to one or more additional RAS variants. G12D, G12V, G12C, G13D, G12R, G12A, G12S, A146T, G13C, K117N, A146V, G12F, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K-, H-, or NRAsamp and HRAS, G13R, G12S, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K-, H-, or NRAsamp and NRAS (G12D, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, A59D, E132K, E49K, T50I, A146V, or A59T).

[0253] In some embodiments, the cancer is non-small cell lung cancer, and the RAS mutations include KRAS mutations such as KRAS G12C, KRAS G12V, or KRAS G12D. In some embodiments, the cancer is colorectal cancer, and the RAS mutations include KRAS mutations such as KRAS G12C, KRAS G12V, or KRAS G12D. In some embodiments, the cancer is pancreatic cancer, and the RAS mutations include NRAS mutations such as NRAS G12D. In some embodiments, the cancer is melanoma.

[0254] In some embodiments, the cancer includes a RAS mutation and an STK11LoF, KEAP1, EPHA5, or NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and includes a KRAS G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and includes a KRAS G12C mutation and an STK11LoF mutation. In some embodiments, the cancer is non-small cell lung cancer and includes a KRAS G12C mutation and an STK11LoF mutation. In some embodiments, the cancer includes a KRAS G13C RAS ​​mutation and an STK11LoF, KEAP1, EPHA5, or NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and includes a KRAS G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and includes a KRAS G12V mutation. In some embodiments, the cancer is colorectal cancer and includes a KRAS G12C mutation. In some embodiments, the cancer is pancreatic cancer and includes a KRAS G12D mutation. In some embodiments, the cancer is pancreatic cancer and contains the KRAS G12V mutation. In some embodiments, the cancer is endometrial cancer and contains the KRAS G12C mutation. In some embodiments, the cancer is gastric cancer and contains the KRAS G12C mutation.

[0255] Methods for detecting mutations in KRAS, HRAS, or NRAS nucleotide sequences are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand higher-order structure polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution thawing assays, and microarray analysis. In some embodiments, real-time PCR is used to evaluate G12C KRAS, HRAS, or NRAS mutations in a sample. In real-time PCR, a fluorescent probe specific to the KRAS, HRAS, or NRAS G12C mutation is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS, HRAS, or NRAS G12C mutations are identified using a method that directly sequences a specific region (e.g., exon 2 or exon 3) within the KRAS, HRAS, or NRAS gene. This method identifies all possible mutations within the sequenced region.

[0256] Methods for detecting mutations in KRAS, HRAS, or NRAS proteins are known to those skilled in the art. These methods include, but are not limited to, the detection of KRAS, HRAS, or NRAS variants using a specific binder (e.g., antibody) for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing. Other methods include ctDNA assays (e.g., Cescon et al., Nature Cancer 1:276-290 (2020)) including TheraScreen PCR, AmoyDx, PNAClamp, RealQuality, EntroGen, LightMix, StripAssay, Hybcell plexA, Devyser, Surveyor, Cobas, and TheraScreen Pyro, as well as the use of highly sensitive diagnostic assays (using CE-IVD markings), such as those described in Domagala, et al., Pol J Pathol 3:145-164 (2012) (the entire text of which is incorporated herein by reference). For example, see also WO2020 / 106640.

[0257] Various samples can be used in methods for determining whether a tumor or cancer contains G12C or other KRAS, HRAS, or NRAS mutations. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a (CTC) sample. In some embodiments, the sample is processed to become a cell lysate. In some embodiments, the sample is processed to become DNA or RNA.

[0258] In some embodiments of any of the methods described herein, prior to being treated with the composition or method of the present invention, the patient has been treated with one or more of the following: chemotherapy, targeted anticancer agents, radiotherapy, and surgery, optionally, the previous treatment was unsuccessful; and / or the patient has undergone surgery, optionally, the surgery was unsuccessful; and / or the patient has been treated with a platinum-based chemotherapeutic agent, optionally, the patient was previously determined not to respond to treatment with the platinum-based chemotherapeutic agent; and / or the patient has been treated with a kinase inhibitor, optionally, the previous treatment with the kinase inhibitor was unsuccessful; and / or the patient has been treated with one or more other therapeutic agents.

[0259] In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering the subject a RAS(ON) inhibitor in combination with one or more therapeutic agents described herein, wherein the subject has one or more tumors that are resistant to or unresponsive to treatment. In various 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, biological agents, small molecule, cell-based therapies, hormone therapy, and immunotherapy. In various embodiments, the treatment is standard therapy, first-line therapy, second-line therapy, or third-line therapy. In various embodiments, the subject has one or more tumors that have progressed between one or more treatments, and the treatment is standard therapy, first-line therapy, second-line therapy, or third-line therapy.

[0260] First-line therapy is defined as treatment administered to a patient with cancer who has received no prior treatment. Second-line therapy is defined as treatment administered to a patient with cancer who has previously received first-line therapy but has experienced disease progression during first-line treatment. Third-line therapy is defined as treatment administered to a patient with cancer who has previously received first and second-line therapy but has experienced disease progression during second-line treatment. Each specific type of cancer has first-line, second-line, and third-line therapies. First, second, and third-line therapies for each type of cancer are publicly known in the relevant art. In addition, FDA-approved drug labels indicate whether a particular drug is approved as a first, second, or third-line therapy.

[0261] To determine the effectiveness of one or more treatments for a target tumor affected by cancer, several criteria and definitions published in the literature can be used. Based on these criteria, a tumor is defined as “responsive,” “stable,” or “progressive” depending on whether it improves, remains the same, or worsens during treatment, respectively.

[0262] Examples of commonly used criteria published in the literature include the Criteria for Evaluation of Solid Tumors (RECIST), the Modified Criteria for Evaluation of Solid Tumors (mRECIST), the PET Criteria for Evaluation of Solid Tumors (PERCIST), the Choi Criteria, the Lugano Criteria, the European Association for the Study of the Liver (EASL) Criteria, the Criteria for Evaluation of Treatment Response to Hepatocellular Carcinoma (RECICL), and the WHO Criteria for Tumor Response.

[0263] In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering the subject a combination therapy described herein, wherein the subject is intolerant to standard, first-line, second-line, or third-line therapies. In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering the subject a combination therapy described herein, wherein the subject has experienced tumor recurrence after surgical resection of the primary tumor. In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering the subject a combination therapy described herein, wherein the subject has a tumor that cannot be surgically removed. In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering the subject a combination therapy described herein, wherein the subject has no available treatment options.

[0264] Some therapies used to treat cancer (e.g., chemotherapy) are cytotoxic and carry significant side effects and toxicities associated with poor outcomes and poor response to treatment. Before administering such treatments, clinicians rely on several assessment tools to help determine the risk of cancer patients experiencing treatment-related toxicities and adverse events. Based on the results of these assessments, cancer patients are considered intolerant to treatment if they are determined to be at high risk of experiencing treatment-related toxicities and adverse events resulting in a poor outcome. Examples of commonly used assessment tools used to determine treatment intolerance include the Karnovsky Performance Status (KPS), the East Coast Cancer Clinical Trials Group Performance Status (ECOG PS), the Timed Get Up and Go (TUG), the Short-Term Physical Ability Battery (SPPB), the Comprehensive Assessment of Geriatric Function (CGA), the Cancer Aging Research Group (CARG) score, and the Chemotherapy Risk Assessment Scale for Elderly Patients (CRASH).

[0265] In some embodiments, the progression of the cancer in question is reduced or inhibited. Disease progression of cancer (e.g., the cancers described herein) can be evaluated by one or more of several established methods. Those skilled in the art can monitor the subject by direct observation to evaluate how the symptoms exhibited by the subject have changed (e.g., reduction or disappearance of symptoms) in response to treatment (e.g., the treatment methods disclosed herein). The subject can also be examined by MRI, CT scan, or PET analysis to determine whether the tumor has metastasized or whether the tumor size has changed (e.g., decreased in response to treatment (e.g., the treatment methods described herein)). Optionally, cells can be extracted from the subject by biopsy or procedure, or tumor DNA can be isolated from the subject's blood, and quantitative biochemical analysis can be performed to assess the relative cancer burden and determine the presence or appearance of specific mutations that may be involved in resistance. Based on these analytical results, those skilled in the art can prescribe higher / lower doses or more frequent / less frequent administration in subsequent treatment rounds.

[0266] In various embodiments, the Disclosure provides a method for treating cancer in a subject, comprising administering the subject a combination therapy disclosed herein. In various embodiments, the administration reduces tumor size or inhibits tumor growth. In various embodiments, the administration induces tumor cell death, apoptosis, or necrosis.

[0267] The methods described herein are intended to reduce tumor size or tumor volume in a subject, or to reduce metastasis in a subject. In various embodiments, the methods reduce tumor size by 10%, 20%, 30%, or more. In various embodiments, the methods reduce tumor size by about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or 100% (or all values ​​and ranges between these values).

[0268] In one embodiment, the present disclosure provides a method for treating a RAS-related disorder in a subject, the pathology of which is partially mediated through increased signaling in the RAS / MAPK pathway. In various embodiments, the method generally involves administering a therapeutically effective dose of the combination therapy disclosed herein to the subject. In some embodiments, the RAS-related disorder is a RAS disease. RAS diseases are a group of hereditary disorders caused by mutations in genes involved in the RAS / MAPK signaling pathway. RAS diseases are characterized by a variety of clinical features and may affect multiple organ systems, including the cardiovascular, musculoskeletal, nervous, and cutaneous systems.

[0269] In some embodiments, the method includes treating RAS diseases selected from Noonan syndrome, Costello syndrome, cardiac-facial-cutaneous syndrome, neurofibromatosis type 1, and Regius syndrome. Each RAS disease has its own unique characteristics, but they all share certain similarities, such as facial deformities, cardiac abnormalities, developmental delays, and an increased risk of certain cancers.

[0270] RAS disease is typically diagnosed through a combination of clinical evaluation, genetic testing, and imaging studies. Treatment and management of RAS disease depend on the specific type and severity of the disorder, but may include medication, surgery, and supportive therapies such as physiotherapy and occupational therapy.

[0271] The compounds described herein can be used in combination with other agents disclosed herein or other suitable agents, depending on the condition being treated. Therefore, in some embodiments, one or more compounds of this disclosure are administered concurrently with other therapies as described herein. When used in combination therapy, the compounds described herein may be administered concurrently with or separately from a second agent. This combined administration may include concurrent administration of the two agents in the same dosage form, concurrent administration in separate dosage forms, and separate administration. That is, the compounds described herein and any agent described herein may be formulated together in the same dosage form and administered concurrently. Alternatively, any of the RAS(ON) inhibitors and therapies described herein may be administered concurrently, and both agents may be present in separate formulations. Another alternative is that the compounds of this disclosure may be administered followed by any of the therapies described herein, and vice versa. In some embodiments of separate administration protocols, any of the RAS(ON) inhibitors and therapies described herein may be administered at intervals of minutes, hours, or days.

[0272] In some embodiments of the methods described herein, the first therapy (e.g., a RAS(ON) inhibitor) and one or more additional therapies are administered simultaneously or sequentially in any order. The first therapeutic agent is administered immediately before or after one or more additional therapies, or up to 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days before or after.

[0273] This disclosure also features a kit comprising (a) a pharmaceutical composition comprising an agent described herein (e.g., a RAS(ON) inhibitor), and (b) a package insert containing instructions for carrying out any of the methods described herein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent described herein (e.g., a RAS(ON) inhibitor), (b) one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents), and (c) a package insert containing instructions for carrying out any of the methods described herein.

[0274] One aspect of the present disclosure relates to combining separate pharmaceutical compositions in the form of a kit, for the purpose of treating a disease or a related condition using a combination of pharmaceutically active compounds that can be administered separately. The kit may comprise two separate pharmaceutical compositions, namely the compounds of the present disclosure, and one or more additional therapies. The kit may comprise containers for housing the separate compositions, such as divided bottles or divided foil packets. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may comprise instructions for using the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing healthcare professional.

[0275] Embodiment Embodiment 1: A method for treating cancer in a subject requiring cancer treatment, the method comprising administering to the subject a therapeutically effective combination of a RAS(ON) inhibitor and an EGFR inhibitor as disclosed herein.

[0276] Embodiment 2: The RAS(ON) inhibitor is RAS MULTI The method according to Embodiment 1, which is an (ON) inhibitor. Embodiment 3: The method according to Embodiment 1 or 2, wherein the RAS(ON) inhibitor is compound RMC-6236 or RMC-7977.

[0277] Embodiment 4: The method according to any one of Embodiments 1 to 3, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, afatinib, or an anti-EGFR antibody.

[0278] Embodiment 5: The method according to any one of Embodiments 1 to 4, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib.

[0279] Embodiment 6: The method according to any one of Embodiments 1 to 4, wherein the EGFR inhibitor is an anti-EGFR antibody comprising panitum ab or cetuximab. Embodiment 7: The method according to any one of Embodiments 1 to 4 or 6, wherein the EGFR inhibitor is cetuximab.

[0280] Embodiment 8: The method according to any one of Embodiments 1 to 7, wherein the cancer includes a RAS mutation. Embodiment 9: The method according to Embodiment 8, wherein the RAS mutation is a KRAS mutation.

[0281] Embodiment 10: The RAS mutation is KRAS G12X A variant of the method described in the embodiment. Embodiment 11: The KRAS G12X The mutation is KRAS G12C or KRAS G12D A variation of the method according to Embodiment 10.

[0282] Embodiment 12: The method according to any one of Embodiments 8 to 11, wherein the therapeutically effective combination further comprises a RAS(ON) mutation-selective inhibitor (e.g., a RAS(ON)G12C selective inhibitor or a RAS(ON)G12D selective inhibitor).

[0283] Embodiment 13. The method according to any one of Embodiments 1 to 12, wherein the cancer is colorectal cancer or pancreatic ductal adenocarcinoma. Embodiment 14: A method for treating cancer in a subject requiring cancer treatment, wherein the method comprises administering to the subject a therapeutically effective combination of a RAS(ON) inhibitor and an EGFR inhibitor as disclosed herein.

[0284] Embodiment 15: The method according to Embodiment 14, wherein the RAS(ON) inhibitor is a RAS(ON)G12C selective inhibitor. Embodiment 16: The method according to Embodiment 14 or 15, wherein the RAS(ON) inhibitor is RMC-6291 or RMC-4998.

[0285] Embodiment 17: The method according to any one of Embodiments 14 to 16, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, afatinib, or an anti-EGFR antibody.

[0286] Embodiment 18: The method according to any one of Embodiments 14 to 17, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib.

[0287] Embodiment 19: The method according to any one of Embodiments 14 to 17, wherein the EGFR inhibitor is an anti-EGFR antibody comprising panitum ab or cetuximab. Embodiment 20: The method according to any one of Embodiments 14 to 17 or 19, wherein the EGFR inhibitor is cetuximab.

[0288] Embodiment 21: The method according to any one of Embodiments 14 to 20, wherein the cancer includes a RAS mutation. Embodiment 22: The method according to Embodiment 21, wherein the RAS mutation is a KRAS mutation.

[0289] Embodiment 23: The KRAS mutation is KRAS G12C A variation of the method described in Embodiment 22. Embodiment 24. The method according to any one of Embodiments 14 to 23, wherein the cancer is colorectal cancer.

[0290] Embodiment 25: A method for treating cancer in a subject requiring cancer treatment, the method comprising administering to the subject a RAS(ON) inhibitor, a chemotherapeutic agent, and an optional therapeutically effective combination of anti-VEGF as disclosed herein.

[0291] Embodiment 26: The method according to Embodiment 1, wherein the RAS(ON) inhibitor is a RAS(ON) multiselective inhibitor and / or a RAS(ON)G12C selective inhibitor. Embodiment 27: The method according to Embodiment 25 or 26, wherein the RAS(ON) multiselective inhibitor is compound RMC-6236 or RMC-7977.

[0292] Embodiment 29: The method according to Embodiment 25 or 26, wherein the RAS(ON)G12C selective inhibitor is RMC-6291 or RMC-4998. Embodiment 28: The method according to any one of Embodiments 25 to 29, wherein the chemotherapy is gemcitabine, paclitaxel, cisplatin, 5-flurouracil, nab-paclitaxel, leucovorin calcium (folic acid), fluorouracil, irinotecan hydrochloride, oxaliplatin, carboplatin, pemetrexed, or a combination thereof.

[0293] Embodiment 29: The method according to any one of Embodiment 28, wherein the chemotherapy is gemcitabine and nab-paclitaxel (Abraxane). Embodiment 30: The method according to any one of Embodiment 28, wherein the chemotherapy is leucovorin calcium (folic acid), fluorouracil, irinotecan, and oxaliplatin.

[0294] Embodiment 31: The method according to any one of Embodiments 25 to 30, wherein the cancer includes a RAS mutation. Embodiment 32: The method according to Embodiment 31, wherein the RAS mutation is a KRAS mutation.

[0295] Embodiment 33: The RAS mutation is KRAS G12X A variation of the method described in Embodiment 32. Embodiment 34: The KRAS G12X The mutation is KRAS G12C or KRAS G12D A variation of the method described in Embodiment 33.

[0296] Embodiment 35: The method according to any one of Embodiments 32 to 34, wherein the therapeutically effective combination further comprises a RAS(ON) mutation-selective inhibitor (e.g., a RAS(ON)G12D-selective inhibitor).

[0297] Embodiment 36. The method according to any one of Embodiments 28 to 35, wherein the cancer is colorectal cancer, pancreatic ductal adenocarcinoma, or non-small cell lung cancer. Embodiment 37: The method according to Embodiment 25, wherein the RAS(ON) inhibitor is RMC-6236, and the chemotherapeutic agent is gemcitabine and nab-paclitaxel or leucovorin calcium (folic acid), fluorouracil, irinotecan, and oxaliplatin.

[0298] Embodiment 38: The method according to Embodiment 37, wherein the cancer is pancreatic ductal adenocarcinoma. Embodiment 39: The method according to Embodiment 38, wherein the cancer includes a KRAS mutation (e.g., KRAS allele amplification).

[0299] Embodiment 40: A method for treating cancer in a subject requiring cancer treatment, wherein the method comprises administering to the subject a therapeutically effective combination of a RAS(ON) inhibitor and a PD-1 / PD-L1 inhibitor as disclosed herein.

[0300] Embodiment 41: The method according to Embodiment 40, wherein the RAS(ON) inhibitor is a RAS(ON) multiselective inhibitor and / or a RAS(ON)G12C selective inhibitor. Embodiment 42: The method according to Embodiment 40 or 41, wherein the RAS(ON) inhibitor is RMC-6236 or RMC-7977.

[0301] Embodiment 43: The RAS(ON)G12C selective inhibitor is RMC-6291 or RMC-4998

[0302] [ka]

[0303] The method according to embodiment 40 or 41. Embodiment 44: The method according to any one of Embodiments 40 to 43, wherein the PD-1 / PD-L1 inhibitor is a PD-1 inhibitor.

[0304] Embodiment 45: The method according to any one of Embodiments 40 to 44, wherein the PD-1 inhibitor is nivolumab, pembrolizumab, semiprimab, tislerizumab, or a biosimilar thereof.

[0305] Embodiment 46: The method according to any one of Embodiments 40 to 45, wherein the PD-1 inhibitor is pembrolizumab. Embodiment 47: The method according to any one of Embodiments 40 to 46, wherein the PD-1 / PD-L1 inhibitor is a PD-L1 inhibitor.

[0306] Embodiment 48: The method according to Embodiment 47, wherein the PD-L1 inhibitor is atezolizumab, avelumab, durvalumab, or a biosimilar thereof. Embodiment 49: The method according to any one of Embodiments 40 to 48, wherein the cancer includes a RAS mutation.

[0307] Embodiment 50: The method according to Embodiment 49, wherein the RAS mutation is a KRAS mutation. Embodiment 51: The RAS mutation is KRAS G12X A variation of the method according to Embodiment 50.

[0308] Embodiment 52: The KRAS G12X The mutation is KRAS G12C or KRAS G12D A variation of the method described in Embodiment 51. Embodiment 53: The method according to any one of Embodiments 45 to 52, wherein the therapeutically effective combination further comprises a RAS(ON) mutation-selective inhibitor (e.g., a RAS(ON)G12D-selective inhibitor).

[0309] Embodiment 54. The method according to any one of Embodiments 40 to 53, wherein the cancer is colorectal cancer, pancreatic ductal adenocarcinoma, or non-small cell lung cancer. Embodiment 55: A method for treating cancer in a subject requiring cancer treatment, wherein the method comprises administering to the subject a therapeutically effective combination of a first RAS(ON) inhibitor and a second RAS(ON) inhibitor, wherein the first RAS(ON) inhibitor and the second RAS(ON) inhibitor are different compounds.

[0310] Embodiment 56: The method according to Embodiment 55, wherein the first RAS(ON) inhibitor is a RAS(ON) multiselective inhibitor. Embodiment 57: The method according to Embodiment 55 or 56, wherein the second RAS(ON) inhibitor is a RAS(ON)G12C selective inhibitor.

[0311] Embodiment 58: The method according to Embodiments 55 to 57, or one thereof, wherein the RAS(ON) inhibitor is RMC-6236. Embodiment 59: The RAS G12C The method according to any one of embodiments 55 to 58, wherein the (ON) inhibitor is RMC-6291.

[0312] Embodiment 60: The method according to any one of Embodiments 55 to 59, wherein the cancer includes a RAS mutation. Embodiment 61: The method according to Embodiment 60, wherein the RAS mutation is a KRAS mutation.

[0313] Embodiment 62: The RAS mutation is KRAS G12X A variation of the method according to Embodiment 61. Embodiment 63: The KRAS G12X The mutation is KRAS G12C or KRAS G12D A variation of the method described in Embodiment 62.

[0314] Embodiment 64. The method according to any one of Embodiments 55 to 63, wherein the cancer is colorectal cancer, pancreatic ductal adenocarcinoma, or non-small cell lung cancer. Embodiment 65: The method according to any one of Embodiments 55 to 64, wherein the cancer is resistant to or has developed resistance to the RAS(ON)G12C selective inhibitor.

[0315] Embodiment 66: The method according to Embodiment 65, wherein the combination of the RAS(ON)G12C selective inhibitor and the RAS(ON) multiselective inhibitor is effective in treating drug-resistant cancer. Embodiment 67: A method for treating cancer in a subject requiring cancer treatment, the method comprising administering to the subject a therapeutically effective combination of a RAS(ON) inhibitor and an mTOR inhibitor as disclosed herein.

[0316] Embodiment 68: The method according to Embodiment 67, wherein the RAS(ON) inhibitor is RMC-6236 or RMC-7977. Embodiment 69: The method according to Embodiment 67 or 68, wherein the mTOR inhibitor is RMC-5552.

[0317] Embodiment 70: The method according to any one of Embodiments 67 to 69, wherein the cancer includes a RAS mutation. Embodiment 71: The method according to Embodiment 70, wherein the RAS mutation is a KRAS mutation.

[0318] Embodiment 72: The RAS mutation is KRAS G12R A variation of the method according to Embodiment 71. Embodiment 73: The method according to any one of Embodiments 67 to 72, wherein the cancer is colorectal cancer, pancreatic ductal adenocarcinoma, or non-small cell lung cancer.

[0319] Embodiment 74: A method for treating cancer in a subject requiring cancer treatment, wherein the method comprises administering to the subject a therapeutically effective combination of a RAS(ON) inhibitor and a PI3K inhibitor disclosed herein.

[0320] Embodiment 75: The method according to Embodiment 74, wherein the RAS(ON) inhibitor is RMC-6236 or RMC-7977. Embodiment 76: The method according to any one of Embodiments 74 to 75, wherein the cancer includes a RAS mutation.

[0321] Embodiment 77: The method according to Embodiment 76, wherein the RAS mutation is a KRAS mutation. Embodiment 78: The RAS mutation is KRAS G12C A variation of the method according to embodiment 77.

[0322] Embodiment 79: The method according to Embodiment 78, wherein the cancer is resistant to a G12C mutation-selective inhibitor. Embodiment 80: The method according to any one of Embodiments 74 to 79, wherein the cancer is colorectal cancer, pancreatic ductal adenocarcinoma, or non-small cell lung cancer.

[0323] Embodiment 81: A method for treating cancer in a subject requiring cancer treatment, the method comprising administering to the subject a therapeutically effective combination of a RAS(ON) inhibitor and a YAP / TAZ-TEAD pathway inhibitor as disclosed herein.

[0324] Embodiment 82: The method according to Embodiment 74, wherein the RAS(ON) inhibitor is RMC-6236 or RMC-7977. Embodiment 83: The method according to Embodiment 81 or 82, wherein the YAP / TAZ-TEAD pathway inhibitor is a pan-TEAD inhibitor.

[0325] Embodiment 84: The method according to any one of Embodiments 81 to 83, wherein the TEAD inhibitor is one or more of VT-107, VT-104, verteporfin, CA3, statin, K-975, or IAG933.

[0326] Embodiment 85: The method according to any one of Embodiments 81 to 84, wherein the cancer includes a RAS mutation. Embodiment 86: The method according to Embodiment 85, wherein the RAS mutation is a KRAS mutation.

[0327] Embodiment 87: The method according to any one of Embodiments 81 to 86, wherein the cancer is colorectal cancer, pancreatic ductal adenocarcinoma, or non-small cell lung cancer. Embodiment 88: A method for treating cancer in a subject requiring cancer treatment, wherein the method comprises administering to the subject a therapeutically effective combination of a RAS(ON) inhibitor and a CDK4 / 6 inhibitor as disclosed herein.

[0328] Embodiment 89: The method according to Embodiment 88, wherein the RAS(ON) inhibitor is RMC-6236 or RMC-7977. Embodiment 90: The method according to Embodiment 88 or 89, wherein the CDK4 / 6 inhibitor is palbociclib.

[0329] Embodiment 91: The method according to any one of Embodiments 88 to 90, further comprising administering a CD40 agonist and / or a PD-1 / PD-L1 inhibitor. Embodiment 92: The method according to Embodiment 91, wherein the CD40 agonist is one or more of CP-870, 893, APX005M, sericrelumab (also known as CP-870, 893), ADC-1013, and CDX-1140.

[0330] Embodiment 93: The method according to any one of Embodiments 88 to 92, wherein the cancer includes a RAS mutation. Embodiment 94: The method according to Embodiment 93, wherein the RAS mutation is a KRAS mutation.

[0331] Embodiment 95: The method according to any one of Embodiments 88 to 94, wherein the cancer is colorectal cancer, pancreatic ductal adenocarcinoma, or non-small cell lung cancer. Embodiment 96: A method for treating cancer in a subject requiring cancer treatment, the method comprising administering to the subject a therapeutically effective combination of i) a RAS(ON) inhibitor and ii) one or more additional therapeutic agents.

[0332] Embodiment 97: A method for treating a RAS-related disorder in a subject requiring treatment for a RAS-related disorder, wherein the method comprises administering to the subject a therapeutically effective combination of i) a RAS(ON) inhibitor and ii) one or more additional therapeutic agents.

[0333] Embodiment 98: A method for inhibiting RAS activity and the activity of one or more target proteins in cells, wherein the method comprises administering to the cells an effective amount combination of i) a RAS(ON) inhibitor and ii) one or more additional therapeutic agents, the one or more additional therapeutic agents modulating the activity of the one or more target proteins.

[0334] Embodiment 99: The method according to any one of Embodiments 96 to 98, wherein the RAS(ON) inhibitor is selected from the RAS(ON) inhibitors described in Section I(A). Embodiment 100: The method according to any one of Embodiments 96 to 98, wherein the one or more additional therapeutic agents are RAS / MAPK pathway inhibitors, kinase inhibitors, receptor tyrosine kinase inhibitors, PI3K / mTOR pathway inhibitors, DNA damage response inhibitors, cell cycle inhibitors, anti-apoptotic protein inhibitors, autophagy inhibitors, macropinocytosis inhibitors, Wnt / beta-catenin pathway inhibitors, JAK / STAT pathway inhibitors, epigenetic modulators, immunotherapies, farnesyltransferase inhibitors, TGF-beta inhibitors, HSP90 inhibitors, GPX4 inhibitors, NRF2 inhibitors, TEAD inhibitors, NOTCH inhibitors, gamma-secretase inhibitors, Hedgehog inhibitors, chemotherapeutic agents, proteasome inhibitors, or any combination thereof.

[0335] Embodiment 101: The method according to Embodiment 100, wherein the RAS / MAPK pathway inhibitor is a RAS(OFF) inhibitor, a SOS1 inhibitor, a SHP2 inhibitor, a MEK inhibitor, a RAF inhibitor, an ERK inhibitor, a MAPK inhibitor, or any combination thereof.

[0336] Embodiment 102: The method according to Embodiment 101, wherein the RAS(OFF) inhibitor is selected from the RAS(OFF) inhibitors described in Section I(b)(i). Embodiment 103: The method according to Embodiment 102, wherein the SOS1 inhibitor is one of the SOS1 inhibitors listed in Section I(b)(ii) (e.g., RMC-5845, RMC-4948, RMC-0331, BI-1701963, BI-3406, SDR5, MRTX0902, BAY-293, or any combination thereof).

[0337] Embodiment 104: The method according to Embodiment 101, wherein the SHP inhibitor is an SHP inhibitor listed in Section I(b)(iii) (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, BBP-398, or any combination thereof).

[0338] Embodiment 105: The method according to Embodiment 101, wherein the MEK inhibitor is one of the MEK inhibitors listed in Section I(b)(iv) (e.g., pimacertib, selumetinib, cobimetinib, trametinib, binimetinib, or any combination thereof).

[0339] Embodiment 106: The method according to Embodiment 101, wherein the RAF inhibitor is one of the RAF inhibitors listed in Section I(b)(v) (e.g., VS-6766, IK-595, vemurafenib, dabrafenib, and encorafenib, or any combination thereof).

[0340] Embodiment 107: The method according to Embodiment 101, wherein the ERK inhibitor is an ERK inhibitor described in Section I(b)(vi) (e.g., ASTX-029, I-75, or a combination thereof).

[0341] Embodiment 108: The method according to Embodiment 101, wherein the MAPK inhibitor is a MAPK inhibitor as described in Section I(b)(vii) (e.g., chilpicertiveb (GS-4875), neflamapidomod (VX-745), or a combination thereof).

[0342] Embodiment 109: The method according to Embodiment 100, wherein the kinase inhibitor is a PKA inhibitor, a FAK inhibitor, a ROCK inhibitor, an MSK1 inhibitor, an RSK inhibitor, an ALK inhibitor, or any combination thereof.

[0343] Embodiment 110: The method according to Embodiment 109, wherein the PKA inhibitor is a PKA inhibitor described in Section I(c)(i) (e.g., H89). Embodiment 111: The method according to Embodiment 110, wherein the FAK inhibitor is one of the FAK inhibitors listed in Section I(c)(ii) (e.g., BI853520, defactinib, GSK2256098, PF-00562271, VS-4718, or any combination thereof).

[0344] Embodiment 112: The method according to Embodiment 109, wherein the ROCK inhibitor is a ROCK inhibitor described in Section I(b)(iii) (e.g., GSK269962A). Embodiment 113: The method according to Embodiment 109, wherein the MSK1 inhibitor is an MSK1 inhibitor listed in Section I(c)(iv) (e.g., SB-747651A, SB747651A, Ro320432, CGP57380, GSK2830371, SR1664, LY-3214996, PFI-4, MSC-2363318A, AS601245, or any combination thereof).

[0345] Embodiment 114: The method according to Embodiment 109, wherein the RSK inhibitor is an RSK inhibitor listed in Section I(c)(v) (e.g., BI-D1870, LJH685, SL0101-1, FMK, BRD7389, BIX02565, LJI308, LJI308-S, LJI308-1, LJH685-S, or any combination thereof).

[0346] Embodiment 115: The method according to Embodiment 115, wherein the ALK inhibitor is an ALK inhibitor listed in Section I(c)(vi) (e.g., crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib (X-396), TAE684, ASP3026, TPX-0131, LDK378 (ceritinib analog), CEP-37440, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, AP26113, or any combination thereof).

[0347] Embodiment 116: The method according to Embodiment 100, wherein the receptor tyrosine kinase inhibitor is an EGFR inhibitor, a HER2 inhibitor, a MET inhibitor, an AXL inhibitor, an IGFR inhibitor, a RET inhibitor, a ROS1 inhibitor, a PDGFR inhibitor, a FGFR inhibitor, a VEGF inhibitor, or any combination thereof.

[0348] Embodiment 117: The method according to Embodiment 116, wherein the EGFR inhibitor is an EGFR inhibitor as described in Section I(d)(i) (e.g., osimertinib, cetuximab, gefitinib (Iressa), erlotinib (Tarceva), razertinib, afatinib (Girotrif), or any combination thereof).

[0349] Embodiment 118: The method according to Embodiment 116, wherein the HER2 inhibitor is a HER inhibitor as described in Section I(d)(ii) (e.g., tucatinib). Embodiment 119: The method according to Embodiment 116, wherein the MET inhibitor is a MET inhibitor as described in Section I(d)(iii) (e.g., crizotinib (Zalkoli), cabozantinib (Cometriq, Cabometyx), capmatinib (Tabrecta), tepotinib (Tepmetco), savolitinib (Volitinib), onarutuzumab (MetMab), foretinib (GSK1363089), MGCD-265 (Amvatinib), SU11274, SU5416, or any combination thereof).

[0350] Embodiment 120: The method according to Embodiment 116, wherein the AXL inhibitor is an ALK inhibitor as described in Section I(d)(iv) (e.g., vemcentib, BGB324, R428, SGI-7079, TP-0903, BMS-777607, UNC2025, TP-0903, or any combination thereof).

[0351] Embodiment 121: The method according to Embodiment 116, wherein the IGFR inhibitor is an IGFR inhibitor as described in Section I(d)(v) (e.g., lincitinib, AXL1717, OSI-906 (lincitinib), BMS-754807, BI836845, AZ12253801, PQIP (pyrrolo[1,2-a]quinoxaline), NVP-AEW541, or any combination thereof).

[0352] Embodiment 122: The method according to Embodiment 116, wherein the RET inhibitor is a RET inhibitor listed in Section I(d)(vi) (e.g., pralcetinib, serpercatinib (LOXO-292), BLU-667, RXDX-105, TPX-0046, GSK3179106, molydastat (BAY85-3934), RPI-1 (Retrofin), or any combination thereof).

[0353] Embodiment 123: The method according to Embodiment 116, wherein the ROS1 inhibitor is a ROS1 inhibitor listed in Section I(d)(vii) (e.g., taretrectinib, DS-6051b, TPX-0131, GZD824, PF-06463922, or any combination thereof).

[0354] Embodiment 124: The method according to Embodiment 116, wherein the PDGFR inhibitor is a PDGFR inhibitor listed in Section I(d)(viii) (e.g., CP-673451, imatinib, nintedanib (Ofev), sunitinib (Stent), pazopanib (Botrian), regorafenib (Stivarga), dasatinib (Sprycel), or any combination thereof).

[0355] Embodiment 125: The method according to Embodiment 116, wherein FGF is an FGF inhibitor as described in Section I(d)(ix) (e.g., futivatinib (TAK-659), erdafitinib (Varvasa), infiglatinib (Truseltiq), Debio1347, and logaratinib (BAY1163877), or any combination thereof).

[0356] Embodiment 126: The method according to Embodiment 116, wherein the VEGF inhibitor is one of the VEGF inhibitors listed in Section I(d)(x) (e.g., bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, pazopanib, or any combination thereof).

[0357] Embodiment 127: The method according to Embodiment 100, wherein the PI3K / mTOR pathway inhibitor is a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, an MNK inhibitor, an eIF4 inhibitor, or any combination thereof.

[0358] Embodiment 128: The method according to Embodiment 127, wherein the PI3K inhibitor is a PI3K inhibitor as described in Section I(e)(i) (e.g., alpelisib, copanlisib, or a combination thereof).

[0359] Embodiment 129: The method according to Embodiment 128, wherein the AKT inhibitor is an AKT inhibitor as described in Section I(e)(ii) (e.g., ipatasertib, GSK-2141795, Akt-1-1, Akt-1-1,2, 1-H-imidazo[4,5-c]pyridinyl derivative, indole-3-carbinol or its derivative, perifosine, phosphatidylinositol ether lipid analog, trisirivine, or any combination thereof).

[0360] Embodiment 130: The method according to Embodiment 127, wherein the mTOR inhibitor is an mTOR inhibitor as described in Section I(e)(iii) (e.g., RMC-5552, PI-103, PP242, PP30, Torin1, FKBP12 enhancer, 4H-1-benzopyran-4-one derivative, rapamycin (sirolimus), rapalog, temsirolimus, everolimus, ridafololimus, AP23464, AP23841, 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (CC1779), 40-epi-(tetrazolito)-rapamycin (ABT578), 32-deoxorapamycin, 16-pentinyloxy-32(S)-dihydrorapanisin, phosphorus-containing rapamycin derivatives, or any combination thereof).

[0361] Embodiment 131: The method according to Embodiment 127, wherein the MNK inhibitor is an MNK inhibitor described in Section I(e)(iv) (e.g., tomibocertib (eFT508), CGP57380, and SEL201, or any combination thereof).

[0362] Embodiment 132: The method according to Embodiment 127, wherein the eIF4 inhibitor is an eIF4A inhibitor or an eIF4G inhibitor. Embodiment 133: The method according to Embodiment 127, wherein the eIF4A inhibitor is an eIF4A inhibitor listed in Section I(e)(v) (e.g., zotatifine (eFT226), silvestrol, pateamine A, locagrate, or any combination thereof).

[0363] The method according to Embodiment 132, wherein the eIF4G inhibitor is patheamine A, hypristanol, or any combination thereof. Embodiment 134: The method according to Embodiment 100, wherein the DNA damage response inhibitor is a Wee1 inhibitor, a CHK inhibitor, an ATM inhibitor, an ATR inhibitor, a PARP inhibitor, a DNA-PK inhibitor, or any combination thereof.

[0364] Embodiment 135: The method according to Embodiment 134, wherein the Wee1 inhibitor is one of the Wee1 inhibitors listed in Section I(f)(i) (e.g., adavocertib, AZD1775, ZNL-02-096, MK-1775, or any combination thereof).

[0365] Embodiment 136: The method according to Embodiment 134, wherein the CHK inhibitor is a CHK1 or CHK2 inhibitor. Embodiment 137: The method according to Embodiment 136, wherein the CHK inhibitor is a CHK inhibitor described in Section I(f)(ii) (e.g., ravsertib, LY2606368, GDC-0575, MK-8776, or any combination thereof).

[0366] Embodiment 138: The method according to Embodiment 137, wherein the ATM inhibitor is an ATM inhibitor listed in Section I(f)(iii) (e.g., M4076, AZD0156, KU-60019, VE-821, or any combination thereof).

[0367] Embodiment 139: The method according to Embodiment 134, wherein the ATR inhibitor is an ATR inhibitor listed in Section I(f)(iv) (e.g., ceraracertib, VX-970, AZD6738, BAY1895344, or any combination thereof).

[0368] Embodiment 140: The method according to Embodiment 134, wherein the PARP inhibitor is a PARP inhibitor as described in Section I(f)(v) (e.g., olaparib, lucaparib, niraparib, veliparib (ABT-888), or any combination thereof).

[0369] Embodiment 141: The method according to Embodiment 134, wherein the DNA-PK inhibitor is one of the DNA-PK inhibitors listed in Section I(f)(vi) (e.g., NU7441, AZD7648, VX-984, M3814, CC-115, SCR7, or any combination thereof).

[0370] Embodiment 142: The method according to Embodiment 100, wherein the cell cycle inhibitor is a CDK inhibitor, an aurora kinase inhibitor, a PLK inhibitor, a KSP inhibitor, or any combination thereof.

[0371] Embodiment 143: The method according to Embodiment 142, wherein the CDK inhibitor is a CDK2 inhibitor, a CDK4 / 6 inhibitor, a CDK7 inhibitor, or a CDK9 inhibitor, or any combination thereof.

[0372] Embodiment 144: The method according to Embodiment 143, wherein the CDK inhibitor is one of the CDK inhibitors listed in Section I(g)(i) (e.g., sericiclib, UCN-01, P1446A-05, PD-0332991, dynacyclib, P27-00, AT-7519, RGB286638, SCH727965, AZD4573, or any combination thereof).

[0373] Embodiment 145: The method according to Embodiment 142, wherein the aurora kinase inhibitor is an aurora kinase inhibitor as described in Section I(g)(ii) (e.g., palbociclib, ribociclib, abemaciclib, aricertib, danucertib, valacertib, MLN8237, or any combination thereof).

[0374] Embodiment 146: The method according to Embodiment 142, wherein the PLK inhibitor is a PLK inhibitor listed in Section I(g)(iii) (e.g., volasertib, onvansertib, BI2536, GSK461364, or any combination thereof).

[0375] Embodiment 147: The method according to Embodiment 142, wherein the KSP inhibitor is one of the KSP inhibitors listed in Section I(g)(iv) (e.g., SB743921, monatrol, S-trityl-L-cysteine ​​(STLC), filanesib (ARRY-520), AMG650, BTB-1, K03861, SJ000291942, or any combination thereof).

[0376] Embodiment 148: The method according to Embodiment 100, wherein the anti-apoptotic inhibitor is a Bcl inhibitor, XIAP inhibitor, survivin inhibitor, Mcl-1 inhibitor, or FLIP inhibitor, or any combination thereof.

[0377] Embodiment 149: The method according to Embodiment 148, wherein the Bcl inhibitor is a BCL inhibitor listed in Section I(g)(v) (e.g., ABT-263, venetoclax (veneclexta), navitoclax (ABT-263), A-1331852, S63845, AT-101, or any combination thereof).

[0378] Embodiment 150: The method according to Embodiment 148, wherein the Mcl-1 inhibitor is one of the Mcl-1 inhibitors listed in Section I(g)(vi) (e.g., AMG-176, MIK665, S63845, or any combination thereof).

[0379] Embodiment 151: The method according to Embodiment 100, wherein the autophagy inhibitor is chloroquine, 3-methyladenine, hydroxychloroquine, spautin-1, SAR405, bafilomycin A1, 5-amino-4-imidazole carboxamidoriboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins, cAMP analogues, LY204002, N6-mercaptopurine riboside, vinblastine, ULK1 inhibitors, VPS inhibitors, or any combination thereof.

[0380] Embodiment 152: The method according to Embodiment 151, wherein the ULK1 inhibitor is a ULK1 / 2 inhibitor. Embodiment 153: The method according to Embodiment 151, wherein the ULK inhibitor is one of the ULK inhibitors listed in Section I(h)(i)(a) (e.g., ULK-101, MRT68921, SBI-0206965, MRT67307, MRT68920, MRT68922, MRT199665, LY3009120, dolsomorphine, or any combination thereof).

[0381] Embodiment 154: The method according to Embodiment 151, wherein the VPS inhibitor is a VPS inhibitor listed in Section I(h)(i)(b) (e.g., PIK-III, VPS34-IN1, SAR405, Spautin-1, NSC185058, or any combination thereof).

[0382] Embodiment 155: The method according to Embodiment 100, wherein the macropinocytosis inhibitor is a macropinocytosis inhibitor as described in Section I(h)(i)(c) (e.g., EIPA (ethyl isopropyl amiloride), wirtmannin, amiloride, apyrimod, Dyngo-4a, latruncrin B, or any combination thereof).

[0383] Embodiment 156: The method according to Embodiment 100, wherein the Wnt / beta-catenin pathway inhibitor is a beta-catenin inhibitor, a PORCN inhibitor, a GSK3 inhibitor, a CLK inhibitor, or any combination thereof.

[0384] The method according to claim 63, wherein the beta-catenin inhibitor is a beta-catenin inhibitor as described in Section I(j)(i) (e.g., tegavivant, foscenvivant, PRI-724 (also known as ICG-001), C-82, BC2059, or any combination thereof).

[0385] Embodiment 157: The method according to Embodiment 156, wherein the PORCN inhibitor is a PORCN inhibitor listed in Section I(j)(ii) (e.g., LGK974 (WNT974), ETC-1922159, CGX1321, CWP232291, or any combination thereof).

[0386] Embodiment 158: The method according to Embodiment 156, wherein the GSK3 inhibitor is a GSK3 inhibitor listed in Section I(j)(iii) (e.g., tidoglucib, radubiglucib, LiCl (lithium chloride), CHIR99021, SB216763, AZD1080, LY2090314, or any combination thereof).

[0387] Embodiment 159: The method according to Embodiment 156, wherein the CLK inhibitor is one of the CLK inhibitors listed in Section I(j)(iv) (e.g., SM08502, SM04690, TG003, KH-CB19, T3.5, CX-4945, or any combination thereof).

[0388] Embodiment 160: The method according to Embodiment 100, wherein the JAK / STAT pathway inhibitor is an inhibitor of JAK1, JAK2, JAK3, STAT3, STAT5, or any combination thereof.

[0389] Embodiment 160: The method according to Embodiment 160, wherein the JAK inhibitor is ruxolitinib, fedratinib, tofacitinib, baricitinib, or any combination thereof.

[0390] Embodiment 161: The method according to Embodiment 160, wherein the STAT inhibitor is SD-36, Stattic, S3I-201, OPB-31121, napabucasin (BBI608), or any combination thereof.

[0391] Embodiment 162: The method according to Embodiment 100, wherein the epigenetic modifier is an HDAC inhibitor, a BET inhibitor, an EZH2 inhibitor, a Co-REST inhibitor, an EP300 inhibitor, an LSD1 inhibitor, a PRMT5 inhibitor, a MAT2A inhibitor, a DOTL1 inhibitor, or any combination thereof.

[0392] Embodiment 163: The method according to Embodiment 100, wherein the farnesyltransferase inhibitor is tipifarnib, ronafarnib, lilapradib, or any combination thereof.

[0393] Embodiment 164: The method according to Embodiment 100, wherein the TGF beta inhibitor is garnicertive (LY2157299), bactocertive (TEW-7197), fresolimmab, reldelimumab, travedersen, curcumin, resveratrol, or any combination thereof.

[0394] Embodiment 165: The method according to Embodiment 100, wherein the HSP90 inhibitor is geldanamycin or a derivative (e.g., 17-AAG, 17-DMAG), KOS953, radicicol or a derivative (e.g., PU-H71), SNX-2112, ganetespib, AT13387, onarespib, luminespib, KW-2478, or any combination thereof.

[0395] Embodiment 166: The method according to Embodiment 100, wherein the GPX4 inhibitor is RSL3, ML162, DPI7, FINO2, MCB-613, CBS9106, ML210, ODSH, TLN232, or any combination thereof.

[0396] Embodiment 167: The method according to Embodiment 100, wherein the NRF2 inhibitor is ML385, brusatol, CDDO-Im, RTA-408, trigonelline, or any combination thereof.

[0397] Embodiment 168: The method according to Embodiment 100, wherein the TEAD inhibitor is VT-107, a pan-TEAD inhibitor, K-975, IAG933, VT-104, verteporfin, CA3, a statin, or any combination thereof.

[0398] Embodiment 169: The method according to Embodiment 100, wherein the notch / gamma-secretase inhibitor is nilogacestat. Embodiment 170: The method according to Embodiment 100, wherein the hedgehog inhibitor is bismodegib, sonimodegib, glassdegib, or any combination thereof.

[0399] Embodiment 171: The method according to Embodiment 100, wherein the chemotherapeutic agent is FOLFOX, FOLFIRI, 5-FU, Tipircil, Trifluridine, TMZ, Docetaxel, Gemcitabine, Abraxane, Paclitaxel, Cisplatin, Carboplatin, Etoposide, or any combination thereof.

[0400] Embodiment 172: The method according to Embodiment 100, wherein the immunotherapy is an immune checkpoint inhibitor, a cytokine inhibitor, a cytokine, a vaccine, an antibody therapy, a bispecific antibody, a cell therapy, or any combination thereof.

[0401] Embodiment 173: The immunotherapy is the method described in Embodiment 172, as shown in Table 1. Embodiment 174: The method according to any one of Embodiments 96 to 98, wherein the one or more additional therapeutic agents include an immune checkpoint inhibitor and a chemotherapeutic agent.

[0402] Embodiment 175: The method according to any one of Embodiments 96 to 98,...

Claims

1. A method for treating cancer in a subject requiring cancer treatment, the method comprising administering to the subject a therapeutically effective combination of i) a RAS(ON) inhibitor and ii) one or more additional therapeutic agents.

2. A method for treating a RAS-related disorder or disorder in a subject requiring treatment, the method comprising administering to the subject a therapeutically effective combination of i) a RAS(ON) inhibitor and ii) one or more additional therapeutic agents.

3. A method for inhibiting RAS activity and the activity of one or more target proteins in cells, the method comprising administering to the cells an effective amount combination of i) a RAS(ON) inhibitor and ii) one or more additional therapeutic agents, wherein the one or more additional therapeutic agents modulate the activity of the one or more target proteins.

4. The method according to any one of claims 1 to 3, wherein the RAS(ON) inhibitor is selected from the RAS(ON) inhibitors described in Section I(A).

5. The method according to any one of claims 1 to 4, wherein the one or more additional therapeutic agents are RAS / MAPK pathway inhibitors, kinase inhibitors, receptor tyrosine kinase inhibitors, PI3K / mTOR pathway inhibitors, DNA damage response inhibitors, cell cycle inhibitors, anti-apoptotic protein inhibitors, autophagy inhibitors, macropinocytosis inhibitors, Wnt / beta-catenin pathway inhibitors, JAK / STAT pathway inhibitors, epigenetic modulators, immunotherapies, farnesyltransferase inhibitors, TGF-beta inhibitors, HSP90 inhibitors, GPX4 inhibitors, NRF2 inhibitors, TEAD inhibitors, NOTCH inhibitors, gamma-secretase inhibitors, Hedgehog inhibitors, chemotherapeutic agents, proteasome inhibitors, or any combination thereof.

6. The method according to claim 5, wherein the RAS / MAPK pathway inhibitor is a RAS(OFF) inhibitor, an SOS1 inhibitor, an SHP2 inhibitor, a MEK inhibitor, an RAF inhibitor, an ERK inhibitor, a MAPK inhibitor, or any combination thereof.

7. The method according to claim 6, wherein the RAS(OFF) inhibitor is selected from the RAS(OFF) inhibitors described in Section I(b)(i).

8. The method according to claim 5, wherein the kinase inhibitor is a PKA inhibitor, a FAK inhibitor, a ROCK inhibitor, an MSK1 inhibitor, an RSK inhibitor, an ALK inhibitor, or any combination thereof.

9. The method according to claim 5, wherein the receptor tyrosine kinase inhibitor is an EGFR inhibitor, a HER2 inhibitor, a MET inhibitor, an AXL inhibitor, an IGFR inhibitor, a RET inhibitor, a ROS1 inhibitor, a PDGFR inhibitor, an FGFR inhibitor, a VEGF inhibitor, or any combination thereof.

10. The method according to claim 5, wherein the PI3K / mTOR pathway inhibitor is a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, a MNK inhibitor, an eIF4 inhibitor, or any combination thereof.

11. The method according to claim 10, wherein the eIF4 inhibitor is an eIF4A inhibitor or an eIF4G inhibitor.

12. The method according to claim 5, wherein the DNA damage response inhibitor is a Wee1 inhibitor, a CHK inhibitor, an ATM inhibitor, an ATR inhibitor, a PARP inhibitor, a DNA-PK inhibitor, or any combination thereof.

13. The method according to claim 5, wherein the cell cycle inhibitor is a CDK inhibitor, an aurora kinase inhibitor, a PLK inhibitor, a KSP inhibitor, or any combination thereof.

14. The method according to claim 13, wherein the CDK inhibitor is a CDK2 inhibitor, a CDK4 / 6 inhibitor, a CDK7 inhibitor, or a CDK9 inhibitor, or any combination thereof.

15. The method according to claim 5, wherein the anti-apoptotic inhibitor is a Bcl inhibitor, a XIAP inhibitor, a survivin inhibitor, a Mcl-1 inhibitor, or a FLIP inhibitor, or any combination thereof.

16. The method according to claim 15, wherein the ULK1 inhibitor is a ULK1 / 2 inhibitor.

17. The method according to claim 5, wherein the Wnt / beta-catenin pathway inhibitor is a beta-catenin inhibitor, a PORCN inhibitor, a GSK3 inhibitor, a CLK inhibitor, or any combination thereof.

18. The method according to claim 5, wherein the JAK / STAT pathway inhibitor is an inhibitor of JAK1, JAK2, JAK3, STAT3, STAT5, or any combination thereof.

19. The method according to claim 5, wherein the epigenetic modifier is an HDAC inhibitor, a BET inhibitor, an EZH2 inhibitor, a Co-REST inhibitor, an EP300 inhibitor, an LSD1 inhibitor, a PRMT5 inhibitor, a MAT2A inhibitor, a DOTL1 inhibitor, or any combination thereof.

20. The method according to claim 5, wherein the immunotherapy is an immune checkpoint inhibitor, a cytokine inhibitor, a cytokine, a vaccine, an antibody therapy, a bispecific antibody, a cell therapy, or any combination thereof.

21. The method according to claim 20, wherein the immunotherapy is as described in Table 1.

22. The method according to any one of claims 1 to 4, wherein the one or more additional therapeutic agents include an immune checkpoint inhibitor and a chemotherapeutic agent.

23. The method according to any one of claims 1 to 4, wherein the combination comprises an EGFR inhibitor and pembrolizumab.

24. The method according to any one of claims 1 to 4, wherein the combination comprises an SHP2 inhibitor, an immune checkpoint inhibitor, and a CTLA-4 inhibitor.

25. The method according to any one of claims 1 to 24, wherein the combination further comprises one or more pharmaceutically acceptable excipients.

26. The method according to any one of claims 1 to 25, wherein the cancer is astrocyte, breast, cervix, colorectal, endometrial, esophageal, gastric, head and neck, hepatocyte, larynx, lung, oral cavity, ovarian, prostate, and thyroid carcinomas and sarcomas. Other cancers include, for example, heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrotoxic hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, lipoma), small intestine (adenocarcinoma) , lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); genitourinary tract: e.g., kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: e.g., liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct cancer Pathways: e.g., gallbladder cancer, duodenal papilla cancer, bile duct cancer; Bones: e.g., osteosarcoma (osteogenic sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: e.g., skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, gliomas), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme) (Oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma); gynecological: for example, uterus (endometrial cancer, uterine cancer, endometrial cancer, cervix (cervical cancer, precancerous cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma);Hematological system: e.g., blood (myeloid leukemia (acute and chronic), acute lymphoblastic myeloproliferative neoplasm), multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: e.g., malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: e.g., neuroblastoma.

27. The method according to claim 26, wherein the cancer is lung cancer (e.g., NSCLC) or gastric cancer (e.g., PDAC, or CRC).

28. The method according to any one of claims 1 to 27, wherein the subject has increased progression-free survival compared to the subject or target population receiving monotherapy with the RAS(ON) inhibitor or monotherapy with one or more additional therapeutic agents.

29. The method according to any one of claims 1 to 27, wherein the subject has an increased probability of relapse-free survival compared to the probability of relapse-free survival of a subject or target population receiving monotherapy with the RAS(ON) inhibitor or monotherapy with one or more additional therapeutic agents.

30. The method according to any one of claims 1 to 27, wherein the subject has increased antitumor activity compared to the antitumor activity in a subject or target population receiving monotherapy with the RAS(ON) inhibitor or monotherapy with one or more additional therapeutic agents.

31. The method according to any one of claims 1 to 27, wherein the one or more additional therapeutic agents synergistically increase the sensitivity of cancer cells to the RAS(ON) inhibitor.

32. The method according to any one of claims 1 to 27, wherein the RAS(ON) inhibitor synergistically increases the sensitivity of cancer cells to the one or more additional therapeutic agents.

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