Methods for treating cancer, for treating a disorder, for inhibiting ras activity in a cell, for increasing the sensitivity of a cell, for treating a rasopathy and for increasing the crosslinking rate of a krasg12c(OFF) inhibitor, pharmaceutical composition and kit

Description

1 / 165 “METHODS FOR TREATING CANCER, FOR TREATING A DISORDER, FOR INHIBITING RAS ACTIVITY IN A CELL, FOR INCREASING THE "Sensitivity of a cell, to treat a rhasopathy and to increase the crosslinking rate of a KRASG12C inhibitor (OFF), pharmaceutical composition and kit" Fundamentals

[0001] Cancer remains one of the deadliest threats to human health. In the U.S., cancer affects nearly 1.3 million new patients each year and is the second leading cause of death after heart disease, accounting for approximately 1 in 4 deaths.

[0002] RAS proteins (KRAS, NRAS, HRAS) regulate cell growth and other cellular functions by converting between a “on” state bound to guanosine triphosphate (GTP) (“RAS(ON)”) and an “off” state bound to guanosine diphosphate (GDP) (“RAS(OFF)”). The active state of RAS is bound to GTP, which is hydrolyzed to the inactive state bound to GDP. RAS proteins have an intrinsically slow hydrolysis rate (Westover et al., Mol Cancer Res (2015) 13 (9): 1325-1335), which is increased in the presence of RAS GTPase activating proteins (GAPs). GDP-bound RAS can be converted to the active state via a slow exchange of GDP for GTP, which is increased by guanine nucleotide exchange factors (GEFs). One way in which oncogenic mutations in RAS increase the amount of RAS protein bound to GTP is by decreasing the rate of intrinsic hydrolysis and reducing sensitivity to GAP-mediated hydrolysis acceleration.Based on these observations, it was historically believed that RAS mutants were constitutively activated in cancer. The amount of active RAS can also be increased through the activation of GEFs within the cell, either through mutations in upstream proteins (e.g., tyrosine kinase receptor mutations) or through non-mutational mechanisms (e.g., reactivation). Petition 870250108725, dated 11 / 27 / 2025, pp. 182 / 351 2 / 165 of the adaptive pathway). In any situation, the increase in GTP-bound RAS levels results in excessive cell proliferation.

[0003] Covalent inhibitors of the “off” form of KRASG12C have demonstrated promising antitumor activity in cancer patients with oncogenic G12C mutations in KRAS. However, therapeutic inhibition of the RAS pathway, while often initially effective, may ultimately prove ineffective because it can, for example, lead to overactivation of RAS signaling through a number of mechanisms, including, for example, the reactivation of RAS signaling through a number of mechanisms, including, for example, the relief of negative feedback mechanisms that naturally operate in these pathways, or it can lead to resistance to RAS(OFF) inhibitors. As a result, cancer cells that were initially sensitive to such inhibitors may become resistant. Most KRAS mutants are susceptible to inhibitors that preferentially target their inactive state, suggesting that they retain the ability to hydrolyze GTP in cancer cells.These findings stimulate the search for pharmacological interventions that improve GTP hydrolysis by mutant KRAS.

[0004] Thus, there is a need in the art for compositions and methods that induce RAS GTP hydrolysis. Furthermore, there is a need for compositions and methods that increase the sensitivity of a cancer cell to a RAS(OFF) inhibitor. Summary

[0005] This disclosure provides compositions and their uses for treating a disease or disorder related to RAS (e.g., cancer), comprising a RAS(ON)GTP hydrolysis-promoting compound. For example, the disclosure provides useful combination therapies for treating cancer, comprising the combination of a RAS(ON)GTP hydrolysis-promoting compound and an additional therapeutic agent (e.g., an inhibitor of Petition 870250108725, dated 11 / 27 / 2025, pp. 183 / 351 3 / 165 RAS(OFF) or a RAS degrader targeting the RAS(OFF) state (“RAS(OFF) degrader”). In any embodiment herein employing a RAS(OFF) inhibitor, a RAS(OFF) degrader may be employed in its place. In some embodiments, the combination comprises two or more therapeutic agents in addition to the RAS(ON)GTP hydrolysis-promoting compound (e.g., a RAS(OFF) inhibitor and an SHP2 inhibitor). In one aspect, the disclosure is based, at least in part, on the observation that contact of a cancer cell with a RAS(ON) GTP hydrolysis-promoting compound and a RAS(OFF) inhibitor work synergistically in reducing cancer cell viability.

[0006] In another aspect, the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a GTP hydrolysis-promoting compound RAS(ON) and an inhibitor of RAS(OFF), wherein the cancer does not comprise a RAS mutation at position 61. In some embodiments, the cancer comprises a RAS mutation (for example, a RAS mutation is at position 12 or 13). In some embodiments, the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer, or uterine cancer. In some embodiments, the cancer is characterized by RAS amplification (RASAMP). In some embodiments, the RASAMP is wild-type RAS or mutant RAS.

[0007] In each of the above embodiments, the binding of the GTP hydrolysis-promoting compound RAS(ON) to RAS GTP (RAS(ON)) alters the position of glutamine 61 of RAS(ON), relative to its position in the absence of the GTP hydrolysis-promoting compound RAS(ON), towards the gamma phosphate of GTP bound to the RAS(ON) protein, thus increasing the rate of GTP hydrolysis relative to the rate of RAS(ON) hydrolysis in the absence of the Petition 870250108725, dated 11 / 27 / 2025, pp. 184 / 351 4 / 165 GTP hydrolysis promoter compound RAS(ON).

[0008] In some embodiments, the GTP hydrolysis promoting compound RAS(ON) is a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof. In exemplary embodiments, the GTP hydrolysis promoting compound RAS(ON) is a compound from Table 1 or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the RAS(OFF) inhibitor is a KRAS(OFF) inhibitor. In some embodiments, the KRAS(OFF) inhibitor is a KRASG12C(OFF) inhibitor. In some embodiments, the KRASG12C(OFF) inhibitor is selected from the group consisting of AMG510 (sotorasib), MRTX849 (adagrasib), MRTX1257, GDC-6036 (divarasib), JDQ443 (opnurasib), ERAS-3490, LY3537982 (olomorasib), BI 1823911, BPI-421286, JAB-3312, JAB-21000, JAB-21822 (glecirasib), D-1553, D3S-001, HBI-2438, HS-10370, MK-1084, YL-15293, BBO-8520 (ON / OFF inhibitor), FMC-376 (ON / OFF inhibitor), GEC255 and GFH925 (IBI351). In some embodiments, the KRAS(OFF) inhibitor is a KRASG12D(OFF) inhibitor. In some embodiments, the KRASG12D(OFF) inhibitor is selected from the group consisting of MRTX1133, MRTX282, JAB-22000, ERAS-4, ERAS-5024, HRS-4642, BI-2852, ASP3082, TH-Z827, TH-7835, QTX-3046, GFH375 (VS-7375), INCB161734 and KD-8.

[0010] In some embodiments, the KRAS(OFF) inhibitor is a KRASG12V(OFF) inhibitor. In specific embodiments, the KRASG12V(OFF) inhibitor is JAB-23000.

[0011] In some embodiments, the KRAS(OFF) inhibitor is a pan-RAS(OFF) inhibitor. In specific embodiments, the panRAS(OFF) inhibitor is JAB-23400, JAB-23425, BI-2493, BI-2865, QTX-3034 (preferably G12D), QTX3544 (preferably G12V), ZG2001, BBO-a, BBO-B or pan KRas-IN1.

[0012] In some embodiments, the hydrolysis-promoting compound Petition 870250108725, dated 11 / 27 / 2025, pp. 185 / 351 5 / 165 of GTP RAS(ON) and the RAS(OFF) inhibitor are administered on the same day. In some embodiments, the GTP hydrolysis-promoting compound RAS(ON) and the RAS(OFF) inhibitor are administered simultaneously or sequentially. In some embodiments, the GTP hydrolysis-promoting compound RAS(ON) and the RAS(OFF) inhibitor are administered on different days.

[0013] In each of the foregoing embodiments, the method may further comprise the administration of additional anticancer therapy. In some embodiments, the additional anticancer therapy is an EGFR inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, an immune checkpoint inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor or a PD-1 inhibitor. In some embodiments, the additional therapy is an SHP2 inhibitor or an SOS1 inhibitor. In each of the above modalities, the SOS1 inhibitor is RMC-5845, RMC-4948, RMC0331, BI-1701963, BI-3406, SDR5, MRTX0902, BAY-293, or any combination thereof.In each of the above embodiments, the SHP2 inhibitor is SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY1971, ERAS-601, SH3809, PF-07284892, BBP-398, or any combination thereof.

[0014] In some embodiments, the subject's cancer progresses with the RAS(OFF) inhibitor (e.g., when the subject receives the RAS(OFF) inhibitor in the absence of a GTP hydrolysis-promoting compound RAS(ON)). In some embodiments, the subject has been treated with a RAS(OFF) inhibitor (e.g., the subject was previously treated with a RAS(OFF) inhibitor, for example, before administration of the GTP hydrolysis-promoting compound). Petition 870250108725, dated 11 / 27 / 2025, pp. 186 / 351 6 / 165 RAS(ON)). In some modalities, the subject has acquired resistance to a RAS(OFF) inhibitor (for example, acquired a mutation that confers resistance to a RAS(OFF) inhibitor, for example, before administration of the GTP hydrolysis-promoting compound RAS(ON)).

[0015] In another aspect, the present disclosure provides methods of treatment for a disorder related to the RAS protein in a subject in need thereof, the methods generally comprising administering to the subject a therapeutically effective amount of a GTP hydrolysis-promoting compound RAS(ON).

[0016] In another aspect, the present disclosure provides a method for treating RASopathy in a subject in need thereof; the methods generally comprise administering to the subject a therapeutically effective amount of a GTP hydrolysis-promoting compound RAS(ON). In some embodiments, RASopathy is cardiofaciocutaneous syndrome, Costello syndrome, Legius syndrome, neurofibromatosis type 1, Noonan syndrome, or capillary-arteriovenous malformation syndrome. In some embodiments, binding the GTP hydrolysis-promoting compound RAS(ON) to RAS(ON) alters the position of glutamine 61 of RAS(ON), relative to the position in the absence of the GTP hydrolysis-promoting compound, toward the gamma phosphate of GTP bound to the RAS(ON) protein, thus increasing the rate of GTP hydrolysis relative to the rate of RAS(ON) hydrolysis in the absence of the GTP hydrolysis-promoting compound RAS(ON).In some modalities, the methods may also include the administration of additional RASopathy therapy. In some modalities, the additional RASopathy therapy is an EGFR inhibitor, a SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a CDK4 / 6 inhibitor, or a... Petition 870250108725, dated 11 / 27 / 2025, pp. 187 / 351 7 / 165 HER2 inhibitor or a combination thereof.

[0017] In yet another aspect, the present disclosure provides methods for inhibiting RAS activity in a cell, the methods generally comprising contacting the cell in which inhibition of RAS activity is desired with an effective amount of a RAS(ON)GTP hydrolysis-promoting compound. In some embodiments, the RAS(ON)GTP hydrolysis-promoting compound is provided in combination with a RAS(OFF) inhibitor, wherein the RAS(ON)GTP hydrolysis-promoting compound synergistically increases the sensitivity of the cell to the RAS(OFF) inhibitor.

[0018] In another aspect, the present disclosure provides methods for increasing the sensitivity of a cell to a RAS(OFF) inhibitor, the methods generally comprising placing the cell in which it is desired to increase sensitivity to the RAS(OFF) inhibitor with an effective amount of a GTP hydrolysis-promoting compound RAS(ON), wherein the GTP hydrolysis-promoting compound RAS(ON) synergistically increases the sensitivity of the cell to the RAS(OFF) inhibitor.

[0019] In another aspect, the present disclosure provides methods for increasing the crosslinking rate of a KRASG12C(OFF) inhibitor to the cysteine ​​residue at position 12 of KRASG12C in a cell, comprising contacting the cell with an effective amount of a GTP hydrolysis-promoting compound RAS(ON).

[0020] In another aspect, the present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a GTP hydrolysis-promoting compound RAS(ON). In some embodiments, the pharmaceutical composition comprises a GTP hydrolysis-promoting compound RAS(ON) and a RAS(OFF) inhibitor.

[0021] In another aspect, the present disclosure provides kits comprising, a) a GTP hydrolysis promoter compound RAS(ON) and b) Petition 870250108725, dated 11 / 27 / 2025, pp. 188 / 351 8 / 165 a RAS(OFF) inhibitor. In some embodiments, the kits also include an insert with instructions for administering the pharmaceutical composition(s).

[0022] It is specifically contemplated that any limitation discussed in relation to one embodiment of the disclosure may be applied to any other embodiment of the disclosure. Furthermore, any compound or composition of the disclosure may be used in any method of disclosure, and any method of disclosure may be used to produce or utilize any compound or composition of the disclosure. Brief Description of the Figures

[0023] FIG. 1 graphically represents the characterization of the activation of RAS GTP hydrolysis by a representative moderate GTP hydrolysis-promoting compound RAS(ON) (Compound E) in several RAS mutants. All RAS mutants show increased hydrolysis in the presence of the GTP hydrolysis-promoting compound RAS(ON), except those with mutations of residue Q61 required for catalytic hydrolysis activity.

[0024] FIG. 2 is a graph showing the characterization of the activation of RAS GTP hydrolysis by various compounds. Compound F represents the class that does not activate GTP hydrolysis by RAS, while the others show varying degrees of activation of RAS GTP hydrolysis.

[0025] FIG. 3A shows a better fit of the concentration-response curves of phospho-(Thr202 / Tyr204; Thr185 / Tyr187)-ERK1 / 2 of Compound C in the presence or absence of 1 μM of RMC-4550 in the KRASG12D mutant cell line, AsPC-1.

[0026] FIG. 3B shows a better fit of the concentration-response curves of phospho-(Thr202 / Tyr204; Thr185 / Tyr187)-ERK1 / 2 of Compound F in the presence or absence of 1 μM of RMC-4550 in the KRASG12D mutant cell line, AsPC-1. Petition 870250108725, dated 11 / 27 / 2025, pp. 189 / 351 9 / 165

[0027] FIG. 3C shows a better fit of the concentration-response curves of Compound C in the presence or absence of 1 μM of RMC-4550 in the KRASG12D mutant cell line, AsPC-1.

[0028] FIG. 3D shows a better fit of the concentration-response curves of Compound C in the presence or absence of 1 μM of RMC-4550 in the mutant cell line KRASG12D, AsPC-1.

[0029] FIG. 4A shows the best fit of the cell viability concentration-response curves of Compound A and MRTX1133 in the KRASG12D mutant cell line, AsPC-1.

[0030] FIG. 4B shows an HSA synergy model of Compound A and MRTX1133 in the KRASG12D mutant cell line, AsPC-1.

[0031] FIG. 4C is a bar graph showing representative points of the synergistic drug combination between Compound A and MRTX1133 in the KRASG12D mutant cell line, AsPC-1.

[0032] FIG. 4D shows the best fit of the cell viability concentration-response curves of Compound A and MRTX-282 in the KRASG12D mutant cell line, AsPC-1.

[0033] FIG. 4E shows an HSA synergy model of Compound A and MRTX-282 in the KRASG12D mutant cell line, AsPC-1.

[0034] FIG. 4F is a bar graph showing representative points of the synergistic drug combination between Compound A and MRTX-282 in the KRASG12D mutant cell line, AsPC-1.

[0035] FIG. 4G shows the best fit of the concentration-response curves of Compound D and MRTX1133 in the KRASG12D mutant cell line, AsPC-1.

[0036] FIG. 4H shows an HSA synergy model of Compound D Petition 870250108725, dated 11 / 27 / 2025, pp. 190 / 351 10 / 165 and MRTX1133 in the KRASG12D mutant cell line, AsPC-1.

[0037] FIG. 4I is a bar graph showing representative points of the synergistic drug combination between Compound D and MRTX1133 in the KRASG12D mutant cell line, AsPC-1.

[0038] FIG. 5A shows the best fit of the cell viability concentration-response curves of Compound A and MRTX1133 in the KRASG12D mutant cell line, HPAC.

[0039] FIG. 5B shows an HSA synergy model of Compound A and MRTX1133 in the KRASG12D mutant cell line, HPAC.

[0040] FIG. 5C is a bar graph showing representative points of the synergistic drug combination between Compound A and MRTX1133 in the KRASG12D mutant cell line, HPAC.

[0041] FIG. 5D shows the best fit of the cell viability concentration-response curves of Compound A and MRTX-282 in the KRASG12D mutant cell line, HPAC.

[0042] FIG. 5E shows an HSA synergy model of Compound A and MRTX-282 in the KRASG12D mutant cell line, HPAC.

[0043] FIG. 5F is a bar graph showing representative points of the synergistic drug combination between Compound A and MRTX-282 in the KRASG12D mutant cell line, HPAC.

[0044] FIG. 6A shows the best fit of the cell viability concentration-response curves of Compound A and MRTX1133 in the KRASG12D, Gp2D mutant cell line.

[0045] FIG. 6B shows an HSA synergy model of Compound A and MRTX1133 in the KRASG12D, Gp2D mutant cell line.

[0046] FIG. 6C is a bar graph showing representative points of the synergistic drug combination between Compound A and MRTX1133 in the KRASG12D, Gp2D mutant cell line. Petition 870250108725, dated 11 / 27 / 2025, pp. 191 / 351 11 / 165

[0047] FIG. 6D shows the best fit of the cell viability concentration-response curves of Compound A and MRTX-282 in the KRASG12D, Gp2D mutant cell line.

[0048] FIG. 6E shows an HSA synergy model of Compound A and MRTX-282 in the KRASG12D, Gp2D mutant cell line.

[0049] FIG. 6F is a bar graph showing representative points of the synergistic drug combination between Compound A and MRTX-282 in the KRASG12D, Gp2D mutant cell line.

[0050] FIG. 7A shows the best fit of the cell viability concentration response curves of Compound D and MRTX-282 in the wild-type RAS cell line, HaCat.

[0051] FIG. 7B shows an HSA synergy model of compound D and MRTX-282 in the wild-type RAS cell line, HaCat.

[0052] FIG. 7C is a bar graph showing representative points of the non-synergistic drug combination of Compound D and MRTX-282 in the wild-type RAS cell line, HaCat.

[0053] FIG. 7D shows the best fit of the cell viability concentration response curves of Compound D and MRTX-282 in the wild-type RAS cell line, HaCat.

[0054] FIG. 7E shows an HSA synergy model of compound D and MRTX-282 in the wild-type RAS cell line, HaCat.

[0055] FIG. 7F is a bar graph showing representative points of the non-synergistic drug combination of Compound D and MRTX-282 in the wild-type RAS cell line, HaCat.

[0056] FIG. 8A shows the best fit of the cell viability concentration-response curves of Compound A and AMG510 in the KRASG12C mutant cell line, MiaPaCa2.

[0057] FIG. 8B shows an HSA synergy model of Compound A Petition 870250108725, dated 11 / 27 / 2025, pp. 192 / 351 12 / 165 and AMG510 in the KRASG12C mutant cell line, MiaPaCa2.

[0058] FIG. 8C is a bar graph showing representative points of the synergistic drug combination between Compound A and AMG510 in the KRASG12C mutant cell line, MiaPaCa2.

[0059] FIG. 8D shows the best fit of the cell viability concentration-response curves of Compound A and MRTX849 in the KRASG12C mutant cell line, MiaPaCa2.

[0060] FIG. 8E shows an HSA synergy model of Compound A and MRTX849 in the KRASG12C mutant cell line, MiaPaCa2.

[0061] FIG. 8F is a bar graph showing representative points of the synergistic drug combination between Compound A and MRTX849 in the KRASG12C mutant cell line, MiaPaCa2.

[0062] FIG. 9A is an immunoblot of MiaPaCa2 cells showing total RAS separated into wild-type HRAS and NRAS, free KRASG12C and sotorasib-covalently modified (crosslinked) KRASG12C.

[0063] FIG. 9B is a bar graph depicting the rate of covalent modification of KRASG12C by sotorasib in MiaPaCa2 cells alone or in combination with Compound A.

[0064] FIG. 10A shows the best fit of a concentration-response curve of the Compound E intracellular RAS-RAF reporter assay in different KRAS mutant proteins.

[0065] FIG. 10B shows the best fit of a concentration-response curve of the intracellular RAS-RAF complex reporter assay of pan KRAS-IN-1 in different KRAS mutant proteins.

[0066] FIG. 10C shows the best fit of a concentration-response curve of the intracellular KRASG12V-RAF reporter assay of pan KRAS-IN-1 in the presence or absence of 1 uM of Compound D. Petition 870250108725, dated 11 / 27 / 2025, pp. 193 / 351 13 / 165

[0067] FIG. 11A shows the best fit of the cell viability concentration-response curves of Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, AsPC-1.

[0068] FIG. 11B shows an HSA synergy model of Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, AsPC-1.

[0069] FIG. 11C is a bar graph showing representative points of the synergistic drug combination between Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, AsPC-1.

[0070] FIG. 11D shows the best fit of the cell viability concentration-response curves of Compound C and pan KRAS-IN-1 in the KRASG12D mutant cell line, AsPC-1.

[0071] FIG. 11E shows an HSA synergy model of Compound C and pan KRAS-IN-1 in the KRASG12D mutant cell line, AsPC-1.

[0072] FIG. 11F is a bar graph showing representative points of the synergistic drug combination between Compound C and pan KRAS-IN-1 in the KRASG12D mutant cell line, AsPC-1.

[0073] FIG. 12A shows the best fit of the cell viability concentration-response curves of Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, Capan-2.

[0074] FIG. 12B shows an HSA synergy model of Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, Capan-2.

[0075] FIG. 12C is a bar graph showing representative points of the synergistic drug combination between Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, Capan-2.

[0076] FIG. 12D shows the best fit of the cell viability concentration-response curves of Compound C and pan KRAS-IN-1 in the KRASG12D mutant cell line, Capan-2.

[0077] FIG. 12E shows an HSA synergy model of the Compound Petition 870250108725, dated 11 / 27 / 2025, pp. 194 / 351 14 / 165 C and pan KRAS-IN-1 in the KRASG12D mutant cell line, Capan-2.

[0078] FIG. 12F is a bar graph showing representative points of the synergistic drug combination between Compound C and pan KRAS-IN-1 in the KRASG12D mutant cell line, Capan-2.

[0079] FIG. 13A shows the best fit of the cell viability concentration-response curves of Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, NCI-H358.

[0080] FIG. 13B shows an HSA synergy model of Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, NCI-H358.

[0081] FIG. 13C is a bar graph showing representative points of the synergistic drug combination between Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, NCI-H358.

[0082] FIG. 13D shows the best fit of the cell viability concentration-response curves of Compound C and pan KRAS-IN-1 in the KRASG12D mutant cell line, NCI-H358.

[0083] FIG. 13E shows an HSA synergy model of Compound C and pan KRAS-IN-1 in the KRASG12D mutant cell line, NCI-H358.

[0084] FIG. 13F is a bar graph showing representative points of the synergistic drug combination between Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, NCI-H358.

[0085] FIG. 14A shows the best fit of the cell viability concentration-response curves of Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, AsPC-1.

[0086] FIG. 14B shows an HSA synergy model of Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, PSN-1.

[0087] FIG. 14C is a bar graph showing representative points of the synergistic drug combination between Compound D and pan KRAS-IN-1 in the KRASG12D mutant cell line, PSN-1. Petition 870250108725, dated 11 / 27 / 2025, pp. 195 / 351 15 / 165

[0088] FIG. 14D shows the best fit of the cell viability concentration-response curves of Compound C and pan KRAS-IN-1 in the KRASG12D mutant cell line, PSN-1.

[0089] FIG. 14E shows an HSA synergy model of Compound C and pan KRAS-IN-1 in the KRASG12D mutant cell line, PSN-1.

[0090] FIG. 14F is a bar graph showing representative points of the synergistic drug combination between Compound C and pan KRAS-IN-1 in the KRASG12D mutant cell line, PSN-1.

[0091] FIG. 15 shows that the orientation of the KRAS Q61 residue differs between an exemplary non-RAS(ON) GTP hydrolysis promoting compound containing a phenol at the A position of a compound of the Formula Ia or Formula Ib type and an exemplary RAS(ON) GTP hydrolysis promoting compound containing a thiazole at the comparable position.

[0092] FIG. 16 shows a scheme that describes the mechanistic rationale for the benefit of the synergistic combination between the GTP hydrolysis-promoting compounds RAS(ON) that accelerate GTP hydrolysis and the nucleotide exchange inhibitor RAS.

[0093] FIG. 17 shows a scheme describing the mechanistic rationale for the benefit of the synergistic combination between GTP hydrolysis-promoting compounds RAS(ON) that accelerate GTP hydrolysis and RAS inhibitors that bind with greater affinity to the RAS(OFF) state [bound to GDP]. Here, a GTP hydrolysis-promoting RAS(ON) compound is shown complexed with cyclophilin A (CypA), which then binds to RAS(ON) to form a tricomplex that catalyzes GTP hydrolysis, converting RAS(ON) to RAS(OFF). The RAS(OFF) generated by this reaction is then bound to the RAS(OFF) inhibitor. Detailed Description

[0094] This disclosure refers, in general, to Petition 870250108725, dated 11 / 27 / 2025, pp. 196 / 351 16 / 165 compositions and methods for modulating RAS activity for cancer treatment. In particular, the present disclosure provides therapies for cancers harboring a RAS mutation. In each embodiment, the cancer does not comprise a mutation at residue Q61. The present disclosure provides methods for treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of a GTP hydrolysis-promoting compound RAS(ON), or a pharmaceutically acceptable salt or pharmaceutical composition thereof, optionally in combination with a RAS(OFF) inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In any embodiment herein employing a RAS(OFF) inhibitor, a RAS(OFF) degrader may be employed in its place.This disclosure also provides methods comprising a GTP RAS(ON) hydrolysis-promoting compound and an additional therapeutic agent (e.g., an SOS1 inhibitor, an SHP2 inhibitor, an RTK inhibitor and / or an additional RAS inhibitor). This disclosure also provides pharmaceutical compositions comprising therapeutically effective amounts of the inhibitors, kits comprising the compositions and methods of use for the same.

[0095] Oncogenic mutations of RAS that increase the proportion of RAS protein in the GTP-bound state limit the amount of GDP-bound RAS available for an RAS(OFF) inhibitor to bind. Without limiting themselves to theory, the inventors postulate that the compounds disclosed herein increase the rate of GTP hydrolysis by oncogenic RAS and / or wild-type RAS, thus increasing the potency of RAS(OFF) inhibitors by increasing GDP-bound RAS levels. The RAS(ON) GTP hydrolysis-promoting compounds disclosed herein show greater selectivity for RASG12X compared to RASWT due to the inherent GAP deficiency of the mutant RAS isoforms. Thus, the RAS(ON)GTP hydrolysis-promoting compounds disclosed herein are Petition 870250108725, dated 11 / 27 / 2025, pp. 197 / 351 17 / 165 useful in the context of RASAMP (e.g., mutant RASAMP) due to the catalytic, rather than stoichiometric, mechanism of target inhibition. Furthermore, the unique profile of the RAS(ON) GTP hydrolysis-promoting compounds disclosed here lends itself to improved tolerability, including in the context of combination therapies, particularly combinations in the pathway. General Methods

[0096] Unless otherwise indicated, the practice of this disclosure will employ conventional techniques of cell culture, molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the scope of technical competence. Such techniques are explained in detail in the literature, such as Molecular Cloning: A Laboratory Manual, third edition (Sambrook et al., 2001) Cold Spring Harbor Press; Oligonucleotide Synthesis (P. Herdewijn, ed., 2004); Animal Cell Culture (RI Freshney, ed., 1987); Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (DM Weir & CC Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JM Miller & MP Calos, eds., 1987); Current Protocols in Molecular Biology (FM Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (JE Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Handbook of Clinical Laboratory Immunology (B. Detrick, NR Rose, and JD Folds eds., 2006); Immunochemical Protocols (J. Pound, ed., 2003); Laboratory Handbook in Biochemistry: Immunology and Biotechnology (A. Nigam and A. Ayyagari, eds. 2007); Handbook of Immunology Methods: The Comprehensive Sourcebook of Techniques (Ivan Lefkovits, ed., 1996); Using Antibodies: A Laboratory Handbook (E. Harlow and D. Lane, eds., 1988); and others. Definitions

[0097] In this request, unless otherwise indicated by the context, (i) Petition 870250108725, dated 11 / 27 / 2025, pp. 198 / 351 18 / 165 the term the / a means one or more; (ii) the term or is used to mean and / or, unless explicitly indicated to refer only to alternatives or to alternatives that are mutually exclusive, although the disclosure supports a definition that refers only to and / or alternatives; (iii) the terms comprising and including are understood as encompassing discriminated components or steps, presented by themselves or in conjunction with one or more additional components or steps; and (iv) where ranges are provided, outcomes are included.

[0098] As used in this document, the term about is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. In certain embodiments, the term about refers to a range of values ​​that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in any direction (greater or less than) of a stated value, unless otherwise indicated or evident from the context (for example, when such a number exceeds 100% of a possible value).

[0099] As used in this document, the term adjacent in the context of describing adjacent atoms refers to divalent atoms that are directly connected by a covalent bond.

[0100] Throughout this specification, unless the context requires otherwise, the words “comprise,” “comprises,” and “comprising” will be understood as implying the inclusion of a stated step or element or group of steps or elements, but not the exclusion of any other step or element or group of steps or elements. “Consisting of” means including, and limited to, what follows the phrase “consisting of.” Thus, the phrase “consisting of” indicates that the listed elements are required or mandatory, and that no other element may be present. “Consisting essentially of” Petition 870250108725, dated 11 / 27 / 2025, pp. 199 / 351 19 / 165 in” is understood to include any elements listed after the phrase and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of” indicates that the listed elements are necessary or mandatory, but that other elements are optional and may or may not be present depending on whether or not they materially affect the activity or action of the listed elements.

[0101] A “compound of the present disclosure” and similar terms used herein, whether explicitly mentioned or not, refer to the GTP RAS(ON) hydrolysis-promoting compounds described herein, including compounds of Formula Ia and Formula Ib and subformulas thereof, and compounds of Table 1 and Table 2, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers) and tautomers thereof.

[0102] Those skilled in the art will appreciate that certain compounds described in this document may exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., where one or more atoms have been replaced by a different isotope of the atom, such as hydrogen replaced by deuterium) forms. Unless otherwise indicated or clear from the context, a represented structure may be understood as representing any isomeric or isotopic form, individually or in combination.

[0103] The compounds described in this document may be asymmetric (e.g., with one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds in this disclosure containing asymmetrically substituted carbon atoms may be isolated in Petition 870250108725, dated 11 / 27 / 2025, pp. 200 / 351 20 / 165 Optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds and the like may also be present in the compounds described in this document, and all such stable isomers are contemplated in this disclosure. Cis and trans geometric isomers of the compounds in this disclosure are described and may be isolated as a mixture of isomers or as separate isomeric forms.

[0104] In some embodiments, one or more compounds represented in this document may exist in different tautomeric forms. As will become clear from the context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. Tautomeric forms result from the exchange of a single bond for an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and ring forms, where a proton can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.In some embodiments, the tautomeric forms may be in equilibrium or sterically linked to a form by appropriate substitution. In certain embodiments, the tautomeric forms result from acetal interconversion.

[0105] Unless otherwise indicated, structures represented in this document are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Isotopes Petition 870250108725, dated 11 / 27 / 2025, pp. 201 / 351 21 / 165 Examples that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I. Isotopically labeled compounds (e.g., those labeled with 3H and 14C) may be useful in assays of the distribution of composite tissues or substrates. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes may be useful for their ease of preparation and detectability. Additionally, substitution with heavier isotopes, such as deuterium (i.e., 2H), can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by carbon enriched with 13C or 14C.Positron-emitting isotopes, such as 15O, 13N, 11C, and 18F, are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labeled compounds are known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared following procedures analogous to those disclosed for the compounds of the present disclosure described herein, replacing an isotopically labeled reagent with a non-isotopically labeled reagent.

[0106] Non-limiting examples of fractions that may contain one or more deuterium substitutions in compounds of the present disclosure, where any R position may be deuterium (D), include: dR _ . R. \ 1 R ° \ R-γγ / -cr3 1 R Η \ / 5 ν' < R-Á and R cr3 .Examples Petition 870250108725, dated 11 / 27 / 2025, pp. 202 / 351 22 / 165 additional items include halves such as Deuteration of similar R1-type fractions, wherein the definition of R1 is found herein. Deuteration of fractions within the substituent W in compounds of the present disclosure is also contemplated, where W is defined herein (see, for example, Formula Ib and its subformulas, as well as specific examples of W described herein). Furthermore, deuteration of available positions in any A portion of compounds of the Formulas described herein is also contemplated. In addition, deuterium substitution may also occur in compounds of the present disclosure at the ligand position.

[0107] In an additional embodiment, substitution by silylation is also contemplated, as in the linker as follows:

[0108] As is known in the art, many chemical entities can adopt a variety of different solid forms, such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present Petition 870250108725, dated 11 / 27 / 2025, pp. 203 / 351 23 / 165 disclosure may be used in any of these forms, including in any solid form. In some embodiments, the compounds described or represented herein may be supplied or used in hydrate or solvate form.

[0109] In several places in this descriptive report, the substituents of compounds in this disclosure are disclosed in groups or in bands. It is specifically intended that this disclosure include any and all individual subcombinations of the members of these groups and bands. For example, the term C1-C6 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound includes a plurality of positions in which substituents are disclosed in groups or in bands, unless otherwise indicated, this disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position.

[0110] The term optionally substituted X (e.g., optionally substituted alkyl) is intended to be equivalent to X, wherein X is optionally substituted (e.g., alkyl, wherein said alkyl is optionally substituted). It is not intended to mean that the feature X (e.g., alkyl) per se is optional. As described in this document, certain compounds of interest may contain one or more optionally substituted moieties. In general, the term substituted, whether preceded by the term optionally or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent, for example, any of the substituents or groups described in this document. Unless otherwise indicated, an optionally substituted group may have a suitable substituent at each substitutable position of the group, and where more than one position in any given structure may be substituted by more than one Petition 870250108725, dated 11 / 27 / 2025, pp. 204 / 351 24 / 165 selected substituent from a specified group, the substituent may be the same or different at each position. For example, in the term optionally substituted C1-C6 alkyl-C2C9 heteroaryl, the alkyl portion, the heteroaryl portion, or both, may be optionally substituted. Combinations of substituents provided for in this disclosure are preferably those that result in the formation of stable or chemically viable compounds. The term stable, as used in this document, refers to compounds that are not substantially altered when subjected to conditions that permit their production, detection and, in certain embodiments, their recovery, purification and use for one or more of the purposes disclosed in this document.

[0111] Suitable monovalent substituents on a replaceable carbon atom of an optionally substituted group may independently be deuterium; halogen; -(CH2)0a4R°; -(CH2)oa4OR°; -0(CH2)oa4Ro; -O-(CH2)0a4C(O)OR°; -(CH2)oa4CH(OR°)2; -(CH2)oa4SR°; -(CH2)oa4Ph, which may be substituted for R°; -(CH2)oa4O(CH2)o-1Ph which may be substituted for R°; -CH=CHPh, which may be substituted for R°; -(CH2)oa4O(CH2)o-1-pyridyl which may be substituted for R°; saturated or unsaturated 4- to 8-membered heterocycloalkyl (e.g., pyridyl); 3- to 8-membered saturated or unsaturated cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2)oa 4N(R°)2; -(CH2)oa 4N(R)C(O)R°; N(R°)C(S)R°; -(CH2)oa 4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)oa 4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; N(R°)N(R°)C(O)OR°; -(CH2)o a 4C(O)R°; -C(S)R°; -(CH2)o a 4C(O)OR°; -(CH2)o a 4-C(O)-N(Ro)2; -(CH2)o a 4-C(O)-N(Ro)-S(O)2-Ro; -C(NCN)NR°2; -(CH2)o a 4C(O)SR°; -(CH2)o a 4C(O)OSíR°3; -(CH2)o a 4OC(O)R°; -OC(0)(CH2)o a 4SR°; SC(S)SR°; -(CH2)o a 4SC(O)R°; -(CH2)o a 4C(O)NR°2; -C(S)NR°2; -C(S)SR°; (CH2)o a 4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; Petição 870250108725, de 27 / 11 / 2025, pág. 205 / 351 25 / 165 C(NOR°)R°; -(CH2)o a 4SSR°; -(CH2)o a 4S(O)2R°; -(CH2)o a 4S(O)2OR°; -(CH2)o a 4OS(O)2R°; -S(O)2NR°2; -(CH2)o a 4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; N(OR°)R°; -C(NOR°)NR°2; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -P(O)(OR°)2; OP(O)R°2; -OP(O)(OR°)2; -OP(O)(OR°)R°, -SiR°3; -(Ci-4 alquileno linear ou ramificado)O-N(R°)2;or -(C1-4 linear or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-6 aliphatic, -CH2Ph, -O(CH2)o-1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a saturated, partially unsaturated, or aryl ring of 3 to 6 members, or an aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R°, taken together with their intervening atom(s), form a saturated, partially unsaturated, or mono- or bicyclic aryl ring of 3 to 12 members having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0112] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intermediate atoms) may independently be halogens, -(CH2)o-2R·, -(haloR·), -(CH2)o-20H, -(CH2)o-20R·, -(CH2)o-2CH(OR')2; -O(haloR·), -CN, -N3, -(CH2)o-2C(O)R·, -(CH2)o-2C(O)OH, -(CH2)o-2C(O)OR·, -(CH2)o-2SR·, -(CH2)o2SH, -(CH2)o-2NH2, -(CH2)o-2NHR·, -(CH2)o-2NRV -NO2, -SiR^3, -OSiR^3, C(O)SR· -(C1-4 linear or branched alkylene)C(O)OR·, or -SSR· wherein each R· is unsubstituted or when preceded by “halo” is substituted only by one or more halogens and is independently selected from aliphatic C1-4, CH2Ph, -O(CH2)o-1Ph, or a 5- to 6-membered ring Saturated, partially unsaturated, or aryl having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S. Petition 870250108725, dated 11 / 27 / 2025, pp. 206 / 351 26 / 165

[0113] Suitable divalent substituents on a saturated carbon atom of an optionally substituted group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =nr*, =nor*, O(C(R*2))2-3O- or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, aliphatic C1-6 which may be substituted as defined below, or a saturated, partially unsaturated or aryl ring of 5 to 6 members with 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.Suitable divalent substituents attached to vicinal replaceable carbons of an optionally substituted group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, aliphatic C1-6 may be substituted as defined below, or a 5- to 6-membered unsubstituted saturated, partially unsaturated or aryl ring with 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0114] Suitable substituents in the aliphatic group of R* include halogen, -R·, -(haloR·), -OH, -OR·, -O(haloR·), -CN, -C(O)OH, -C(O)OR·, NH2, -NHR·, -NR^2, or -NO2, wherein each R • is unsubstituted or, where preceded by halo, is substituted, only by one or more halogens and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a partially unsaturated, saturated, 5- to 6-membered unsubstituted aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0115] Suitable substituents on a replaceable nitrogen of an optionally substituted group include -Rt, -NR^, -C(O)Rt -C(O)ORt C(O)C(O)Rt, -C(O)CH2C(O)Rt -S(O)2Rt -S(O)2NR^, -C(S)NR^2, -C(NH)NRt2, or -N(Rt)S(O)2Rt; wherein each Rt is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, -OPh unsubstituted, or unsubstituted 3 to 6 membered, partially unsaturated, Petition 870250108725, dated 11 / 27 / 2025, pp. 207 / 351 27 / 165 or an aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of Rt, taken together with their intervening atom(s) form a partially unsaturated, saturated, bicyclic or monocyclic aryl ring of 3 to 12 members having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0116] Suitable substituents on the aliphatic group of Rt include halogen, -R, -(haloR·), -OH, -OR·, -OR·, -O(haloR·), -CN, -C(O)OH, C(O)OR·, -NH2, -NHR·, -NRV or -NO2, wherein each R· is unsubstituted or, where preceded by halo, is substituted, only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a partially unsaturated, saturated, 5- to 6-membered unsubstituted aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of Rt include =O and =S.

[0117] Those skilled in the art, reading this disclosure, will appreciate that certain compounds described herein may be supplied or used in any of a variety of forms, such as, for example, salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a specific form of that compound. In some embodiments, reference to a particular compound may refer 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 than 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 an isomer Petition 870250108725, dated 11 / 27 / 2025, pp. 208 / 351 28 / 165 conformational ((Z) or (E)) isomer of a double bond may be considered a different form from one containing the other conformational ((E) or (Z)) isomer of the double bond; a preparation in which one or more atoms is a different isotope from that present in a reference preparation may be considered a different form.

[0118] As used in this document, the term administration refers to the administration of a composition (e.g., a compound, or a preparation that includes a compound as described in this document) to a subject or system. Administration also includes administering a prodrug derivative or analogue of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which may form an equivalent amount of the active compound within the subject's body. Administration to an animal subject (e.g., a human) may be done by any appropriate route.For example, in some modalities, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreous.

[0119] The term acetyl, as used in this document, refers to the -C(O)CH3 group.

[0120] The term alkoxy, as used in this document, refers to an -O-C1-C20 alkyl group, wherein the alkoxy group is bonded to the rest of the compound via an oxygen atom.

[0121] The term alkyl, as used in this document, refers to a saturated, linear or branched monovalent hydrocarbon group containing from 1 to 20 (e.g., from 1 to 10 or from 1 to 6) carbons. In some embodiments, an alkyl group is unbranched (i.e., it is linear); in some Petition 870250108725, dated 11 / 27 / 2025, pp. 209 / 351 In 29 / 165 embodiments, an alkyl group is branched. Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n- and isopropyl, n-, sec-, iso- and tert-butyl, and neopentyl.

[0122] The term alkylene, as used in this document, represents a saturated divalent hydrocarbon group derived from a saturated linear or branched chain hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like. The term Cx-Cy alkylene represents alkylene groups with x and y carbons between them. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C10, C2-C20, C2-C6, C2-C10, or C2-C20 alkylene). In some embodiments, the alkylene may be further replaced by 1, 2, 3 or 4 substituent groups, as defined in this document.

[0123] The term alkenyl, as used in this document, represents monovalent linear or branched chain groups of, unless otherwise indicated, 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyls include cis and trans isomers. The term alkenylene, as used in this document, represents divalent linear or branched chain groups of, unless otherwise indicated, 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0124] The term alkynyl, as used in this document, represents monovalent linear or branched chain groups of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl and 1-propynyl.

[0125] The term amino, as used in this document, represents -N(RT)2, for example, -NH2 and -N(CH3)2. Petition 870250108725, dated 11 / 27 / 2025, pp. 210 / 351 30 / 165

[0126] The term aminoalkyl, as used in this document, represents an alkyl moiety substituted at one or more carbon atoms with one or more amino moieties.

[0127] The term amino acid, as used in this document, refers to a molecule with a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), wherein the amino acid is linked to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain). As used in this document, the term amino acid in its broadest sense refers to any compound or substance that can be incorporated into a polypeptide chain, for example, through the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid.Standard amino acid refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. Exemplary 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, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0128] An “amino acid substitution,” as used herein, refers to the replacement of a wild-type amino acid in a protein with a non-wild-type amino acid. Amino acid substitutions can result from genetic mutations and can alter one or more properties of the protein (for example, they can confer altered binding affinity or specificity, altered enzyme activity, altered structure, or altered function). Petition 870250108725, dated 11 / 27 / 2025, pp. 211 / 351 31 / 165

[0129] The term aryl, as used in this document, represents a monovalent monocyclic, bicyclic, or multicyclic ring system formed by carbon atoms, in which the ring attached to the pendant group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. An aryl ring may be attached to its pendant group on any heteroatom or carbon ring atom that results in a stable structure, and any of the ring atoms may be optionally substituted unless otherwise indicated.

[0130] The term Co, as used in this document, represents a connection. For example, part of the term -N(C(O)-(Co-C5 alkylene-H)- includes N(C(O)-(Co alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0131] The terms carbocyclic and carbocyclyl, as used in this document, refer to an optionally substituted, monovalent C3-C12 monocyclic, bicyclic, or tricyclic ring structure, which may be bridged, fused, or spirocyclic, in which all rings are formed from carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctinyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like. A carbocyclic ring may be attached to its pendant group on any ring atom resulting in a stable structure, and any of the ring atoms may be optionally substituted unless otherwise indicated.

[0132] The term carbonyl, as used in this document, represents a C(O) group, which can also be represented as C=O.

[0133] The term carboxyl, as used in this document, means -CO2H, (C=O)(OH), COOH or C(O)OH or the non-protonated counterparts.

[0134] The term “combined therapy” refers to a method of Petition 870250108725, dated 11 / 27 / 2025, pp. 212 / 351 32 / 165 treatment that includes administering to a subject at least two therapeutic agents, optionally as one or more pharmaceutical compositions, as part of a therapeutic regimen. For example, a combination therapy may include the administration of a single pharmaceutical composition including at least two therapeutic agents and one or more pharmaceutically acceptable vehicles, excipients, diluents, or surfactants. A combination therapy may include the administration of two or more pharmaceutical compositions, each composition including one or more therapeutic agents and one or more pharmaceutically acceptable vehicles, excipients, diluents, or surfactants. In several embodiments, at least one of the therapeutic agents is a GTP RAS(ON) hydrolysis promoter compound (for example, any one or more of these GTP RAS(ON) hydrolysis promoter compounds disclosed herein or known in the art).In several embodiments, at least one of the therapeutic agents is a KRAS(OFF) inhibitor (for example, any one or more of the KRAS(OFF) inhibitors disclosed herein or known in the art). In some embodiments, at least one of the therapeutic agents is a KRASG12C(OFF) inhibitor (for example, any one or more of the KRASG12C(OFF) inhibitors disclosed herein or known in the art). In some embodiments, at least one of the therapeutic agents is a KRASG12D(OFF) inhibitor (for example, any one or more of the KRASG12D(OFF) inhibitors disclosed herein or known in the art). In some embodiments, at least one of the therapeutic agents is a KRASG12V(OFF) inhibitor (for example, any one or more of the KRASG12V(OFF) inhibitors disclosed herein or known in the art). In some embodiments, at least one of the therapeutic agents is a panRAS(OFF) inhibitor (for example, any one or more of the pan-RAS(OFF) inhibitors disclosed herein or known in the art).The two or more agents may optionally be administered simultaneously (as a single dose). Petition 870250108725, dated 11 / 27 / 2025, pp. 213 / 351 33 / 165 composition or as separate compositions) or sequentially (as separate compositions). The therapeutic agents can be administered in an effective amount. The therapeutic agent can be administered in a therapeutically effective amount. In some modalities, the effective amount of one or more therapeutic agents may be less when used in combination therapy than the therapeutic amount of the same therapeutic agent when used as monotherapy, for example, due to an additive or synergistic effect of the combination of two or more therapeutic agents.

[0135] The term cyan, as used in this document, represents the -CN group.

[0136] The term cycloalkyl, as used herein, represents a monovalent saturated cyclic hydrocarbon group that may be bridged, fused or spirocyclic having three to eight ring carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloheptyl.

[0137] The term cycloalkenyl, as used herein, represents a monovalent, non-aromatic, saturated cyclic hydrocarbon group that may be bridged, fused or spirocyclic having three to eight ring carbons, unless otherwise specified, and containing one or more carbon-carbon double bonds.

[0138] The term diastereomer, as used in this document, means stereoisomers that are not mirror images of each other and are non-superimposable on each other.

[0139] As used in this document, the term dosage form refers to a physically distinct unit of a compound (for example, a compound of the present invention) for administration to a subject. Each unit contains a predetermined amount of compound. In some embodiments, such amount is a unit dosage quantity (or Petition 870250108725, dated 11 / 27 / 2025, pp. 214 / 351 34 / 165 (an integer fraction thereof) appropriate for administration in accordance with a dosage regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosage regimen). Those skilled in the art recognize that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0140] As used herein, the term dosage regimen refers to a set of unit doses (usually more than one) that are administered individually to a subject, normally separated by periods of time. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dosage regimen, which may involve one or more doses. In some embodiments, a dosage regimen includes a plurality of doses, each of which is separated from the other by a period of time of the same length; in some embodiments, a dosage regimen includes a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosage regimen are of the same single dose amount. In some embodiments, different doses within a dosage regimen are of different amounts.In some embodiments, a dosing regimen includes a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen includes a first dose in a first dose amount, followed by one or more additional doses in a second dose amount equal to the first dose amount. In some embodiments, a dosing regimen is correlated with an outcome. Petition 870250108725, dated 11 / 27 / 2025, pp. 215 / 351 35 / 165 desired or beneficial when administered to a relevant population (i.e., it is a therapeutic dosage regimen).

[0141] The term “disorder” is used in this disclosure to mean, and is used interchangeably with the terms disease, condition or illness, unless otherwise indicated.

[0142] The term enantiomer, as used in this document, means each individual optically active form of a disclosure compound, with an optical purity or enantiomeric excess (as determined by standard methods in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

[0143] The term guanidinyl refers to a group with the structure: %ÁNÀN· RR, where each R is, independently, any chemically viable substituent described in this document.

[0144] The term aminoalkyl, as used in this document, represents an alkyl moiety substituted at one or more carbon atoms with one or more amino moieties.

[0145] The term haloacetyl, as used in this document, refers to an acetyl group in which at least one of the hydrogens has been replaced by a halogen.

[0146] The term haloalkyl, as used in this document, represents an alkyl moiety substituted on one or more carbon atoms with one or more of the same different halogen moieties.

[0147] The term halogen, as used in this document, represents a halogen selected from bromine, chlorine, iodine or fluorine.

[0148] The term heteroalkyl, as used in this document, refers to an alkyl group, as defined in this document, in which Petition 870250108725, dated 11 / 27 / 2025, pp. 216 / 351 36 / 165 minus one carbon atom has been replaced by a heteroatom (for example, an O, N, or S atom). The heteroatom can appear in the middle or at the end of the radical.

[0149] The term heteroaryl, as used in this document, represents a monovalent, monocyclic or polycyclic ring structure containing at least one fully aromatic ring: that is, they contain 4n+2 pi electrons within the monocyclic or polycyclic ring system and contain at least one ring heteroatom selected from N, O or S in that aromatic ring. Exemplary unsubstituted heteroaryl groups are 1 to 12 carbons (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10 or 2 to 9). The term heteroaryl includes bicyclic, tricyclic and tetracyclic groups in which any of the above heteroaromatic rings is fused to one or more aryl or carbocyclic rings, for example, a phenyl ring or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl.A heteroaryl ring can be attached to its pendant group on any ring atom that results in a stable structure, and any of the ring atoms can be optionally substituted unless otherwise specified. In some embodiments, the heteroaryl is substituted by 1, 2, 3, or 4 substituent groups.

[0150] The term “heterocycloalkyl”, as used in this document, represents a monovalent, monocyclic, bicyclic, or polycyclic ring system, which may be bridged, fused, or spirocyclic, in which at least one ring is non-aromatic and in which the non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has from zero to two double bonds, and the 6- and 7-membered rings have from zero to three double bonds. Exemplary unsubstituted heterocycloalkyl groups are Petition 870250108725, dated 11 / 27 / 2025, pp. 217 / 351 37 / 165 from 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term heterocycloalkyl also represents a heterocyclic compound with a bridged multicyclic structure in which one or more carbons or heteroatoms bridge to two non-adjacent members of a monocyclic ring, for example, a quinuclidinyl group. The term heterocycloalkyl includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, for example, an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, a pyridine ring, or a pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphtiridine.A heterocycloalkyl ring can be attached to its pendant group on any ring atom that results in a stable structure, and any of the ring atoms can optionally be substituted unless otherwise specified.

[0151] The term “hydroxy”, as used in this document, represents an -OH group.

[0152] The term hydroxyalkyl, as used in this document, represents an alkyl moiety substituted at one or more carbon atoms by one or more -OH moieties.

[0153] The term isomer, as used in this document, means any tautomer, stereoisomer, atropiomer, enantiomer, or diastereomer of any compound of the disclosure. It is recognized that the compounds of the invention may have one or more chiral centers or double bonds and therefore exist as stereoisomers, such as double-bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the invention, the chemical structures represented in this document and therefore the Petition 870250108725, dated 11 / 27 / 2025, pp. 218 / 351 38 / 165 compounds of the invention encompass all corresponding stereoisomers, i.e., both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates. Enantiomeric and stereoisomeric mixtures of the disclosed compounds can typically be resolved into their component enantiomers or stereoisomers by well-known methods such as chiral gas chromatography, chiral high-performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0154] The term “inhibitor” means a compound or agent (e.g., peptide, antibody) that prevents a biomolecule (e.g., a protein) from completing or initiating a reaction. An inhibitor may inhibit a reaction by competitive, uncompetitive, or non-competitive means, for example. With respect to its binding mechanism, an inhibitor may be an irreversible inhibitor or a reversible inhibitor. Exemplary inhibitors include, but are not limited to, nucleic acids, DNA, RNA, shRNA, siRNA, proteins, protein mimetics, peptides, peptidomimetics, antibodies, small molecules, chemicals, analogs that mimic the binding site of an enzyme, receptor, or other protein. In some embodiments, the inhibitor is a small molecule, for example, a low molecular weight organic compound, for example, an organic compound with a molecular weight (MW) less than 1200 Daltons (Da). In some embodiments, the MW is less than 1100 Da.In some modes, MW is less than 1000 Da. In some modes, MW is less than 900 Da. In some modes, MW is... Petition 870250108725, dated 11 / 27 / 2025, pp. 219 / 351 39 / 165 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 between 600 Da and 700 Da, inclusive. In some embodiments, the MW range of the small molecule is between 600 Da and 800 Da, inclusive. Small molecule inhibitors include cyclic and acyclic compounds. Small molecule inhibitors include natural products, derivatives, and analogs. Small molecule inhibitors may include a covalent cross-linking group capable of forming a covalent cross-link, for example, with an amino acid side chain of a target protein.

[0155] As used in this document, the term linker refers to a divalent organic moiety that connects a first moiety (e.g., a macrocyclic moiety) to a second moiety (e.g., a crosslinking group). In some embodiments, the linker results in a compound capable of achieving an IC50 of 2 uM or less in the Ras-RAF breakthrough assay protocol provided here: The aim of this biochemical assay is to measure the ability of the test compounds to facilitate the formation of a ternary complex between a nucleotide-loaded Ras isoform and cyclophilin A; the resulting ternary complex disrupts binding to a BRAFRBD construct, inhibiting Ras signaling through a RAF effector.

[0156] In assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl2, unlabeled Cyclophilin A, His6-K-Ras-GMPPNP (or another Ras variant), and GST-BRAFRBD are combined in a 384-well assay plate at final concentrations of 25 pM, 12.5 nM, and 50 nM, respectively. The compound is present in the wells of the plate as a 10-point dilution series in 3-fold increments starting with a final concentration of 30 pM. After incubation at 25°C for 3 hours, a Petition 870250108725, dated 11 / 27 / 2025, pp. 220 / 351 A 40 / 165 mixture of anti-His Eu-W1024 and anti-GST allophycocyanin is then added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction is incubated for a further 1.5 hours. The TR-FRET signal is read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that facilitate the breakdown of a Ras:RAF complex are identified as those that cause a decrease in the TR-FRET ratio relative to the DMSO control wells.

[0157] In some embodiments, the ligand comprises 20 or fewer linear atoms. In some embodiments, the ligand comprises 15 or fewer linear atoms. In some embodiments, the ligand comprises 10 or fewer linear atoms. In some embodiments, the ligand has a molecular weight less than 500 g / mol. In some embodiments, the ligand has a molecular weight less than 400 g / mol. In some embodiments, the ligand has a molecular weight less than 300 g / mol. In some embodiments, the ligand has a molecular weight less than 200 g / mol. In some embodiments, the ligand has a molecular weight less than 100 g / mol. In some embodiments, the ligand has a molecular weight less than 50 g / mol.

[0158] The term “mutation,” as used herein, indicates any modification of a nucleic acid or polypeptide that results in an altered nucleic acid or polypeptide. The term “mutation” may include, for example, point mutations, deletions or insertions of single or multiple residues in a polynucleotide, which includes alterations arising within a protein-coding region of a gene, as well as alterations in regions outside a protein-coding sequence, such as, but not limited to, regulatory or promoter sequences, as well as chromosomal amplifications or breaks or translocations. In specific embodiments, the mutation results in an amino acid substitution in the encoded protein.

[0159] A “patient” or “subject” is a mammal, for example, a Petition 870250108725, dated 11 / 27 / 2025, pp. 221 / 351 41 / 165 human, mouse, rat, guinea pig, dog, cat, horse, cow, pig or non-human primates, such as a monkey, chimpanzee, baboon or rhesus.

[0160] The term “prevent” or “prevent” in relation to a subject refers to preventing a disease or disorder from afflicting the subject. Prevention includes prophylactic treatment. For example, prevention may include administering to the subject a compound disclosed herein before the subject is afflicted by a disease, and the administration will prevent the subject from being afflicted by the disease.

[0161] As used in this document, the term pharmaceutical composition refers to a compound, such as a compound of this disclosure, or a pharmaceutically acceptable salt, formulated together with a pharmaceutically acceptable excipient.

[0162] A pharmaceutically acceptable excipient, as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially non-toxic and non-inflammatory in a subject. Typical excipients include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, colorants (colors), emollients, emulsifiers, bulking agents (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, absorbents, suspending or dispersing agents, sweeteners or waters for hydration.Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), 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. Petition 870250108725, dated 11 / 27 / 2025, pp. 222 / 351 42 / 165 polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, starch glycolate, 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 variety of useful agents and materials 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, a composition includes at least two different pharmaceutically acceptable excipients.

[0163] The term pharmaceutically acceptable salt, as used in this document, refers to salts of the compounds described herein that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, and are proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008. Salts may be prepared in situ during the final isolation and purification of the compounds described herein or separately by reaction of a free base group with a suitable organic acid.

[0164] The terms “RAS inhibitor” and “inhibitor of [a] RAS” are used interchangeably to refer to any inhibitor that targets, i.e., selectively binds to or inhibits, a RAS protein. Petition 870250108725, dated 11 / 27 / 2025, pp. 223 / 351 43 / 165

[0165] As used herein, the term “RAS(OFF) inhibitor” refers to an inhibitor that targets, i.e., selectively binds to or inhibits the active state of GTP-bound RAS (e.g., selective over the inactive state of GDP-bound RAS). Inhibition of the inactive state of GDP-bound RAS includes, for example, sequestering the inactive state by inhibiting the exchange of GDP for GTP, thereby inhibiting RAS from adopting the active conformation. In certain embodiments, RAS(OFF) inhibitors may also bind to or inhibit the inactive state of GDP-bound RAS (e.g., with a lower affinity or inhibition constant than for the inactive state of GTP-bound RAS). A RAS(OFF) inhibitor may be selective for mutants, such as selective for a G12C, G12D, or G12V mutant. A RAS(OFF) inhibitor can be selective for more than one mutant, or selective for one or more mutants and for the wild type (in either case, a “pan-RAS(OFF)” inhibitor).Methods for measuring RAS(OFF) inhibition are known in the art.

[0166] As used herein, the term “RAS(ON) inhibitor” refers to an inhibitor that targets, i.e., selectively binds to or inhibits the active state of GTP-bound RAS (e.g., selective over the inactive state of GDP-bound RAS). Inhibition of the active state of GTP-bound RAS includes, for example, the inhibition of oncogenic signaling of the active state of GTP-bound RAS. In some embodiments, the RAS(ON) inhibitor is an inhibitor that selectively binds to and inhibits the active state of GTP-bound RAS. In certain embodiments, RAS(ON) inhibitors may also bind to or inhibit the inactive state of GDP-bound RAS (e.g., with a lower affinity or inhibition constant than for the inactive state of GTP-bound RAS). RAS(ON) inhibitors are non-covalent ligands of the GTP-bound RAS form, and those knowledgeable in the field are familiar with methods for determining whether cross-linking has occurred.In some embodiments, a RAS(ON) inhibitor does not comprise a crosslinking group, such as groups of. Petition 870250108725, dated 11 / 27 / 2025, pp. 224 / 351 44 / 165 crosslinking found in the art (e.g., WO 2020 / 132597, WO 2021 / 091982, WO 2021 / 091967, WO 2022 / 235864, WO 2022 / 235870, WO 2023 / 060253, PCT / US2023 / 037057 and WO 2023 / 133543). In some embodiments, a RAS(ON) inhibitor has a molecular weight between 800 and 1200 Da, inclusive. The term RAS(ON) inhibitor includes, without limitation, any one or more RAS(ON) inhibitors selected from the RAS(ON) inhibitors disclosed in WO 2021 / 091956, WO 2022 / 060836, U.S. Provisional Application Serial Number 63 / 351146, or WO 2023 / 240263, each of which is incorporated by reference in its entirety, or a combination of any of these RAS(ON) inhibitors. In some embodiments, compounds from WO 2021 / 091956, WO 2022 / 060836, and WO 2023 / 240263 comprising a phenol at the A position of each are excluded. Methods for determining RAS(ON) inhibition are known in the art. See, for example, WO 2021 / 091956, WO 2022 / 060836 and WO 2023 / 240263.

[0167] As used herein, a “RAS(ON) GTP hydrolysis promoter compound” refers to a tricomplex-forming compound that, when linked to a tricomplex (i.e., CYPA-GTP RAS(ON) hydrolysis promoter compound-RAS(ON) isoform), exhibits a RAS(ON) GTP hydrolysis rate that is greater than the intrinsic hydrolysis rate of the mutant RAS(ON) isoform (RASMUT) and / or wild-type RAS isoform (RASWT) in the absence of the compound. In some embodiments, a RAS(ON) GTP hydrolysis promoter compound exhibits a hydrolysis rate that is greater than 14x the intrinsic hydrolysis rate (a “strong hydrolysis”). In some embodiments, a RAS(ON) GTP hydrolysis promoter compound exhibits a hydrolysis rate that is 5-14x the intrinsic hydrolysis rate (a “moderate hydrolyzer”).In some embodiments, a GTP hydrolysis-promoting compound RAS(ON) exhibits a hydrolysis rate that is greater than 1x the intrinsic hydrolysis rate, but less than 5x the intrinsic hydrolysis rate (a “weak hydrolyzer”). Petition 870250108725, dated 11 / 27 / 2025, pp. 225 / 351 45 / 165 In some embodiments, KRASG12V is the isoform used to determine a strong hydrolyzer, a moderate hydrolyzer, or a weak hydrolyzer. Hydrolysis measurement methods are known in the art, such as those described herein. In some embodiments, a GTP RAS(ON) hydrolysis-promoting compound is a RAS(ON) inhibitor. All GTP RAS(ON) hydrolysis-promoting compounds retain a catalytic water in the vicinity of the GTP gamma phosphorus (distance < 5 angstroms) and position the delta carbon of Q61 of RAS(ON) within 8 angstroms of the gamma phosphorus: these parameters can be determined by a specialist in the field. Further descriptions of GTP RAS(ON) hydrolysis-promoting compounds are described herein.

[0168] As used herein, a “RAS(OFF) degrader” is a RAS degrader that targets the OFF state. Such degraders are known in the art. Non-limiting examples of RAS(OFF) degraders can be found in one or more of the following applications: WO 2024055112, WO 2024054625, WO 2024050742, WO 2024044334, WO 2024040080, WO 2024034657, WO 2024034593, WO 2024034591, WO 2024034123, WO 2024029613, WO 2024020159, WO 2024019103, WO 2024017392, WO 2023185864, WO 2023171781, WO 2023141570, WO 2023138524, WO 2023130012, WO 2023116934, WO 2023099620, WO 2023081476, WO 2023077441 and CN 115785199, each of which is incorporated herein by reference in its entirety.

[0169] The terms “RAS pathway” and “RAS / MAPK pathway” are used interchangeably herein to refer to a downstream signal transduction cascade of multiple cell surface growth factor receptors in which RAS activation (and its various isoforms and allotypes) is a central event that drives a variety of cellular effector events that determine cell proliferation, activation, differentiation, mobilization, and other functional properties. SHP2 transmits positive signals from growth factor receptors. Petition 870250108725, dated 11 / 27 / 2025, pp. 226 / 351 46 / 165 growth for the RAS activation / deactivation cycle, which is modulated by guanine nucleotide exchange factors (GEFs, such as SOS1) that carry GTP into the RAS to produce functionally active GTP-bound RAS, as well as GTPase activator proteins (GAPs, such as NF1) that facilitate signal termination 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 kinases, from which further signals emanate for various cellular effector functions.

[0170] The term stereoisomer, as used in this document, refers to all possible different isomeric and conformational forms that a compound may possess (for example, a compound of any formula described in this document), in particular all stereochemically and conformationally possible isomeric forms, all diastereomers, enantiomers or conformers of the basic molecular structure, including atropisomers. Some compounds in this disclosure may exist in different tautomeric forms, all of which are included within the scope of this disclosure.

[0171] The term sulfonyl, as used in this document, represents an -S(O)2- group.

[0172] A “therapeutic agent” is any substance, for example, a compound or composition, capable of treating a disease or disorder. In some embodiments, therapeutic agents that are useful in connection with the present disclosure include RAS inhibitors and chemotherapeutic agents against cancer. Many of these therapeutic agents are known in the art and are disclosed herein.

[0173] The term therapeutically effective amount means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder or condition, in accordance with a regimen of Petition 870250108725, dated 11 / 27 / 2025, pp. 227 / 351 47 / 165 therapeutic dosage, to treat the disease, disorder, or condition. In some modalities, a therapeutically effective amount is one that reduces the incidence or severity or delays the onset of one or more symptoms of the disease, disorder, or condition. Those skilled in the art will realize that the expression therapeutically effective amount does not, in fact, require that successful treatment be achieved in a particular individual. Instead, a therapeutically effective amount may be the amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. It is specifically understood that particular subjects may, in fact, be refractory to a therapeutically effective amount.In some modalities, reference to a therapeutically effective amount may be a reference to an amount measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will realize that, in some modalities, a therapeutically effective amount may be formulated or administered in a single dose. In some modalities, a therapeutically effective amount may be formulated or administered in a plurality of doses, for example, as part of a dosing regimen.

[0174] The term thiocarbonyl, as used in this document, refers to a -C(S)- group.

[0175] The term treatment (also treat or treating), in its broadest sense, refers to any administration of a substance (for example, a compound of the present disclosure) that partially or completely relieves, improves, alleviates, inhibits, delays the onset, reduces the severity, or reduces the incidence of one or more symptoms, features, or causes of a specific disease, disorder, or condition. In some modalities, such treatment may Petition 870250108725, dated 11 / 27 / 2025, pp. 228 / 351 48 / 165 may be administered to a subject who does not exhibit signs of the relevant disease, disorder, or condition, or to a subject who exhibits only early signs of the disease, disorder, or condition. Alternatively or additionally, in some modalities, treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder, or condition. In some modalities, treatment may be given to a subject who has been diagnosed as suffering from the relevant disease, disorder, or condition. In some modalities, treatment may be given to a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder, and / or condition.

[0176] The term “tri-complex” refers to having a mechanism of action that involves the formation of a high-affinity three-component complex between a synthetic ligand (e.g., a RAS(ON)GTP hydrolysis-promoting compound) and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest, RAS, and a widely expressed cytosolic chaperone protein, cyclophilin A. Such tri-complexes are known in the art. See, for example, WO 2020 / 132597, WO 2021 / 091956, WO 2021 / 091967, WO 2021 / 091982, WO 2022 / 060836, WO 2022 / 235864, WO 2022 / 235 / 870, WO 2023 / 060253, WO 2023 / 133543 and WO 2023 / 240263.

[0177] The term wild type refers to an entity with a structure or activity as found in nature in a normal state or context (as opposed to mutant, diseased, altered, etc.). Those of common skill in the technique will appreciate that wild-type genes and polypeptides generally exist in multiple different forms (e.g., alleles). I. Compositions

[0178] Compounds that promote hydrolysis are provided here Petition 870250108725, dated 11 / 27 / 2025, pp. 229 / 351 49 / 165 of RAS(ON) GTP and its uses. Pharmaceutical compositions including one or more of these compounds, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, are also provided. RAS(ON) GTP hydrolysis-promoting compounds can be used in methods of RAS modulation (e.g., in a subject or in a cell) and cancer treatment methods, as described herein. This disclosure provides, inter alia, compositions, methods, and kits for treating or preventing a disease or disorder (e.g., cancer) with a RAS(ON) GTP hydrolysis-promoting compound in combination with a RAS(OFF) inhibitor.

[0179] It is well established in the literature that RAS proteins (KRAS, H-RAS, and N-RAS) play an essential role in several human cancers and are therefore appropriate targets for anticancer therapy. In fact, mutations in RAS proteins are responsible for approximately 30% of all human cancers in the United States, many of which are fatal. Dysregulation of RAS proteins by activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations in RAS are frequently found in human cancer. RAS converts between a GDP-bound “off” state and a GTP-bound “on” state. The conversion between states is facilitated by the interaction between a guanine nucleotide exchange factor (GEF) protein (e.g., SOS1), which loads RAS with GTP, and a GTPase activating protein (GAP) (e.g., NF1), which hydrolyzes GTP, thus inactivating RAS.Furthermore, the protein tyrosine phosphatase-2 (SHP2) containing the SH2 domain associates with the receptor signaling apparatus and becomes active after RTK activation, thus promoting RAS activation. Mutations in RAS proteins can lock the protein in the "on" state, resulting in a constitutively active signaling pathway that leads to uncontrolled cell growth. For example, activation mutations at codon 12 in RAS proteins work. Petition 870250108725, dated 11 / 27 / 2025, pp. 230 / 351 50 / 165 inhibits the intrinsic and GAP-dependent hydrolysis rates of GTP, significantly distorting the population of mutant RAS proteins to the “on” (GTP-bound) state (RAS(ON)), leading to oncogenic MAPK signaling. Notably, RAS exhibits a picomolar affinity for GTP, allowing RAS to be activated even in the presence of low concentrations of this nucleotide. Mutations in codons 13 (e.g., G13D) and 61 (e.g., Q61K) of RAS are also responsible for oncogenic activity in some cancers. a) Compounds that promote the hydrolysis of GTP RAS(ON)

[0180] The compositions of the present disclosure may include one or more RAS(ON)GTP hydrolysis-promoting compounds. One RAS(ON) GTP hydrolysis-promoting compound of the present disclosure forms a high-affinity tricomplex with two intracellular proteins that do not interact under normal physiological conditions: RAS and a widely expressed cytosolic chaperone, cyclophilin A (CypA). In addition, the present disclosure provides non-covalent binding of RAS by a RAS(ON) GTP hydrolysis-promoting compound to promote a catalytically competent orientation of RAS(ON) in which the glutamine side chain 61 (Q61) coordinates a catalytic water to promote nucleophilic attack on the gamma-phosphate-bound GTP. See FIG. 15.

[0181] Consequently, a RAS(ON)GTP hydrolysis-promoting compound is provided here, having the structure of Formula Ia: r16χΐ Formula IA Petition 870250108725, dated 11 / 27 / 2025, pp. 231 / 351 51 / 165 or a pharmaceutically acceptable salt thereof, wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally C2-C4 optionally substituted alkylene, C1C4 optionally substituted heteroalkylene, or C2-C4 optionally substituted alkenylene; G is optionally C1-C4 optionally substituted alkylene, C1C4 optionally substituted alkenylene, C1-C4 optionally substituted heteroalkylene, -C(O)O-CH(R6)- where C is bonded to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R7R8)-, C1-C4 optionally substituted heteroalkylene, or 3- to 8-membered heteroarylene; swIp (Switch I / P-loop) is an organic moiety that binds non-covalently to both the Switch I binding pocket and residues 12 or 13 of the Ploop of a Ras protein (see, for example, Johnson et al., 292:12981-12993 (2017), incorporated herein by reference); X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is, independently, H or C1-C4 alkyl optionally substituted; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are, independently, C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; Petition 870250108725, dated 11 / 27 / 2025, pp. 232 / 351 52 / 165 R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2 is absent, it is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is missing, or R2 and R3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, it is hydrogen, halogen, cyano or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, C1-C3 alkoxy. Petition 870250108725, dated 11 / 27 / 2025, pp. 233 / 351 or R7 and R8 combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are, independently, hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R10a is hydrogen or halo; and R16 is hydrogen or C1-C3 alkyl.

[0182] In some modalities, the disclosure presents a Petition 870250108725, dated 11 / 27 / 2025, pp. 234 / 351 54 / 165 compound of structural formula Ib that does not crosslink with a RAS protein: FC6χΐ Formula Ib or a pharmaceutically acceptable salt thereof, wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is optionally C2-C4 optionally substituted alkylene, C1C4 optionally substituted heteroalkylene, or C2-C4 optionally substituted alkenylene; If B is absent, it is -NH-, -N(CH3)-, -O-, -CH(R9)- or >C=CR9R9' where the carbon is bonded to the carbonyl atom of -N(R11)C(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene or optionally substituted 5- to 6-membered heteroarylene; G is optionally C1-C4 optionally substituted alkylene, C1C4 optionally substituted alkenylene, C1-C4 optionally substituted heteroalkylene, -C(O)O-CH(R6)- where C is bonded to -C(R7R8)-, -C(O)NH-CH(R6)- where C is bonded to -C(R7R8)-, C1-C4 optionally substituted heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or is a ligand; Petition 870250108725, dated 11 / 27 / 2025, pp. 235 / 351 55 / 165 W is hydrogen, cyano, optionally substituted amino, optionally substituted amide, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted C0C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 3- to 10-membered heteroaryl, wherein W does not crosslink with RAS; Z is -C(O)- or -S(O)2-; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is, independently, H or C1-C4 alkyl optionally substituted; Y1 is C, CH, or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl. Petition 870250108725, dated 11 / 27 / 2025, pp. 236 / 351 56 / 165 optionally replaced, or R1 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent or R2 and R3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, it is hydrogen, halogen, cyano or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkyne, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or Petition 870250108725, dated 11 / 27 / 2025, pp. 237 / 351 57 / 165 R7 and R8 combine with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R7 and R8 are, independently, hydrogen, halo, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl. R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R9e L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; and Petition 870250108725, dated 11 / 27 / 2025, pp. 238 / 351 58 / 165 R16 is hydrogen or C1-C3 alkyl.

[0183] In some embodiments, the disclosure provides a compound of Formula Ia Formula Ia wherein R1 is cyano, halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., C1-C6 haloalkyl or C1-C6 fluoroalkyl), optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2 is absent, is hydrogen, halogen (e.g., fluoro), C1-C6 alkyl, optionally substituted C1-C6 haloalkyl (e.g., C1-C6 fluoroalkyl), optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Petition 870250108725, dated 11 / 27 / 2025, pp. 239 / 351 59 / 165 R3 is absent or R2 and R3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, it is hydrogen, halogen (e.g., fluoro), cyano, or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, halogen (e.g., fluoro), C1-C4 alkyl optionally substituted with halogen (e.g., fluoro), cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; Y5 is CH, CH2, CF, CHF, CF2, or N; Y6 is C(O), CH, CF, CH2, CF2, or N; and the remaining variables are as defined above.

[0184] In some forms, the disclosure provides a Formula Ib compound Formula Ia wherein R1 is cyano, halogen (e.g., fluoro), optionally substituted C1-C6 alkyl (e.g., C1-C6 haloalkyl or C1-C6 fluoroalkyl), optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, aryl Petition 870250108725, dated 11 / 27 / 2025, pp. 240 / 351 60 / 165 with 6 to 10 members optionally replaced or heteroaril with 5 to 10 members optionally replaced, or R1 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; If R2 is absent, it is hydrogen, halogen (e.g., fluoro), C1-C6 alkyl, optionally substituted C1-C6 haloalkyl (e.g., C1-C6 fluoroalkyl), optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent or R2 and R3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, it is hydrogen, halogen (e.g., fluoro), cyano, or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, halogen (e.g., fluoro), C1-C4 alkyl optionally substituted with halogen (e.g., fluoro), cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; Y5 is CH, CH2, CF, CHF, CF2, or N; Y6 is C(O), CH, CF, CH2, CF2, or N; and the remaining variables are as defined above.

[0185] In some modalities, A is one of the following: Petition 870250108725, dated 11 / 27 / 2025, pp. 241 / 351 61 / 165

[0186] In some modalities, A is one of the following:

[0187] In some modes, R1 is

[0188] In some modalities, R1 is / the R17

[0189] In some modalities, R1 is / the R21where Z1 is N or CH; m is 1 or 2; R18, R19, R20, and R21 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R18 and R20 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl group. Petition 870250108725, dated 11 / 27 / 2025, pp. 242 / 351 62 / 165 optionally substituted 3- to 8-membered heterocycloalkyl; or R20 and R21 combine with the atoms to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl group; or R19 and R20 combine with the atoms to which they are attached to form an optionally substituted 4- to 8-membered cycloalkyl heterocycloalkyl.

[0190] In some modalities, R1 is / the R18.

[0191] In some modalities, R1 is / O R18.

[0192] In some embodiments, R18 is methyl.

[0193] In some modes, R1 is W N-? O or W

[0194] In some embodiments, B is -CHR9-. In some embodiments, R9 is optionally substituted C1-C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, B is optionally substituted 6-membered arylene. In some embodiments, B is absent.

[0195] In some forms, the binder has a Formula II structure: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k-A2 Petition 870250108725, dated 11 / 27 / 2025, pp. 243 / 351 63 / 165 Formula II where A1 is a linkage between the ligand and B; A2 is a linkage between W and the ligand; B1, B2, B3, and B4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C3 cycloalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1;and D1 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted 3- to 14-membered heterocycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C10 polyethylene glycolene, or optionally substituted C1-C10 heteroalkylene, or a chemical linkage A1-(B1)f-(C1)g-(B2)ha-(B3)i-(C2)j-(B4)k-A2;

[0196] In some embodiments, the ligand is acyclic. In some embodiments, the ligand has the structure of Formula IIa: R14 Formula IIa where Xa is absent or is N; R14 is absent, is hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C3 cycloalkyl; and L2 is absent, it is -C(O)-, -SO2-, optionally C1-C4 alkylene Petition 870250108725, dated 11 / 27 / 2025, pp. 244 / 351 64 / 165 substituted or optionally substituted C1-C4 heteroalkylneocarbon, in which at least one of Xa, R14 or L2 is present.

[0197] In some embodiments, the ligand is or comprises a cyclic group. In some embodiments, the ligand has the structure of Formula IIb: / r15\ Jn-xK-lA ' 0 Formula IIb where o is 0 or 1; Xbé C(O) or SO2; R15 is hydrogen or optionally substituted C1-C6 alkyl; Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; and L3 is absent, it is -C(O)-, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.

[0198] In some forms, the ligand is absent.

[0199] In some embodiments, W is hydrogen. In some embodiments, W is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyridine, or optionally substituted phenyl. In some embodiments, W is optionally substituted amino. In some embodiments, W is optionally substituted amide. In some embodiments, W is optionally substituted C1-C4 alkoxy. In some embodiments, W is optionally substituted C1-C4 alkyl. In some embodiments, W is optionally substituted C1-C4 hydroxyalkyl. In some embodiments, W is C1 Petition 870250108725, dated 11 / 27 / 2025, p. 245 / 351 65 / 165 C4 aminoalkyl optionally substituted. In some embodiments, W is C1-C4 haloalkyl optionally substituted. In some embodiments, W is C1-C4 guanidinoalkyl optionally substituted. In some embodiments, W is optionally substituted 3- to 11-membered C0-C4 alkyl heterocycloalkyl. In some embodiments, W is optionally substituted 3- to 10-membered cycloalkyl. In some embodiments, W is optionally substituted 3- to 10-membered heteroaryl. In some embodiments, W is optionally substituted 6- to 10-membered aryl.

[0200] In some embodiments, a strong hydrolyzer is contemplated, wherein the strong hydrolyzer is a compound comprising one of the following nuclei: It is one of the following: acceptable among them. In some modalities, it is one of the following:

[0201] In some forms, a moderate hydrolyzer is Petition 870250108725, dated 11 / 27 / 2025, pp. 246 / 351 66 / 165 contemplated, wherein the moderate hydrolyzer is a compound comprising one of the following cores: in which and: S, or a pharmaceutically acceptable salt thereof. Examples of such compounds can be found in, for example, WO 2021 / 091956, WO 2022 / 060836 and WO 2023 / 240263, each of which is incorporated herein by reference in its entirety.

[0202] In some embodiments, a weak hydrolyzer is contemplated, wherein the weak hydrolyzer is a compound comprising one of the following nuclei: where it is one of the following: Petition 870250108725, dated 11 / 27 / 2025, pp. 247 / 351 67 / 165 or a pharmaceutically acceptable salt thereof. Examples of such compounds can be found in, for example, WO 2021 / 091956, WO 2022 / 060836 and WO 2023 / 240263, each of which is incorporated by reference in its entirety.

[0203] A compound with the structure of is also provided here. Formula Ic, Id or Ie: or a pharmaceutically acceptable salt thereof, wherein: in the Ic formula: Rwé methylcyclopropyl; Ry is CH3, CH2F, CHF or CHF3; Rz is hydrogen or N-methylpiperazinyl; R10 is H; and A1 is -CH2-, -O- or -NCH3; in Formula ID: Rwé methylcyclopropyl or dimethylcyclopropyl; Ry is CH3; Rz is hydrogen or N-methylpiperazinyl; Petition 870250108725, dated 11 / 27 / 2025, pp. 248 / 351 68 / 165 R10 is H; and A1 is -CH2, -O- or -NCH3; or in the formula le: either the E or Z double bond is present; Rwé methylcyclopropyl or dimethylcyclopropyl; Rv is CH3; Rzé hydrogen or / V-methylpiperazinyl; R10 is H; and A1é -CH2-.

[0204] In some embodiments, a strong hydrolyzer is employed in a method disclosed herein. In some embodiments, a moderate hydrolyzer is not employed in a method of the present invention. In some embodiments, a weak hydrolyzer is not employed in a method of the present invention.

[0205] In some embodiments, a compound from this disclosure is selected from Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound from this disclosure is selected from Table 1, or a pharmaceutically acceptable salt or atropisomer thereof. Table 1: Exemplary GTP hydrolysis-promoting compounds RAS(ON) that are strong hydrolyzers Ex. # Structure 1 (Compound A) j haa.' L_ í H γ 2 (Compound B) ο Η γ Μ—if ÜAJJ Petition 870250108725, dated 11 / 27 / 2025, pp. 249 / 351 69 / 165 Ex. # Structure 3 (Compound C) Λα ' λ- Λ v ΟλαΛ O k 4 5 6(Compound D) / 7 ΛΛν MeO L- 1 * γ <f

[0206] In some embodiments, a GTP RAS(ON) hydrolysis-promoting compound from this disclosure is selected from Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a compound from this disclosure is selected from Table 2, or a pharmaceutically acceptable salt or atropisomer thereof. Table 2: Exemplary GTP hydrolysis-promoting compounds RAS(ON) that are moderate hydrolyzers or weak hydrolyzers Ex. # Structure 8 (Compound E) Moderate νίΛ” · V·”0 4 9 Weak \> ο=ξ o zx / —z —z ( ''—\ A? \ / O u. O x—V >=i γ'^-A / Z-^'u· Petition 870250108725, dated 11 / 27 / 2025, pp. 250 / 351 70 / 165 Ex. # Structure 10 Moderate V w O ZI c- s 09 \ / u. '°u 11 Moderate vGv0 ο 0 0 / 12 Moderate Çpç / 13 Moderate 'Czv 14 Moderate < 0” 15 Moderate >2xx .x ​​Λς| / 16 Moderate γΟγ» 0 0 O0ÁA < Λ (Ύ V—. Ί^Ξ 1 Q^ÒO^ ß Q 17 Weak °ΥΌν° ß V” N^'s Jl N—( / / ]| g । Petition 870250108725, dated 11 / 27 / 2025, pp. 251 / 351 71 / 165 Ex. # Structure 18 Weak O 'i / y- 19 ​​Moderate O 7—sf ui Xx 20 Weak °γθγ> 0 / C Γ η V í 21 Weak yQ-y o / 22 Weak vQv ° 7 (Ά H /

[0207] The RAS(ON) GTP hydroxylysis promoting compounds described in this document can be made from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic processes.

[0208] The compounds of the present invention can be prepared by methods known to those skilled in the art, such as those disclosed in WO 2021 / 091956, WO 2022 / 060836 and WO 2023 / 240263, in combination with known synthetic organic chemistry techniques, the disclosure of each of which is incorporated herein by reference. As an example, the compounds of the present invention can be synthesized using Petition 870250108725, dated 11 / 27 / 2025, pp. 252 / 351 72 / 165 the methods described in the Schemes below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. These methods include, but are not limited to, those methods described in the Schemes below. Scheme 1. General synthesis of macrocyclic esters

[0209] A general synthesis of macrocyclic esters is outlined in Scheme 1. An appropriately substituted indolyl boronic ester (1) can be prepared in four steps starting from protected 3-(5-bromo-2-iodo-1H-indol-3-yl)2,2-dimethylpropan-1-ol and appropriately substituted boronic acid, including palladium-mediated coupling, alkylation, deprotection and palladium-mediated borylation reactions.

[0210] Methyl-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (3) can be prepared by coupling (S)-2-amino-3-(4-bromothiazol-2-yl)propanoic acid (2) with methyl (S)-hexahydropyridazine-3-carboxylate.

[0211] The final macrocyclic esters can be made by coupling methyl-amino-3-(4-bromothiazol-2-yl)propanoyl)hexa Petition 870250108725, dated 11 / 27 / 2025, pp. 253 / 351 73 / 165 hydropyridazine-3-carboxylate (3) and an appropriately substituted indolyl boronic ester (1) in the presence of a Pd catalyst followed by hydrolysis and macrolactonization steps to result in a suitably protected macrocyclic intermediate (5). Deprotection and coupling with an appropriately substituted carboxylic acid (or other coupling partner) can result in a macrocyclic product. Further deprotection or functionalization steps might be required to produce a final compound 6.

[0212] Furthermore, with respect to Scheme 1, the thiazole may be replaced by an alternative optionally substituted 5- to 6-membered heteroarylene, or an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene (e.g., morpholino) or optionally substituted 6-membered arylene (e.g., phenyl). Scheme 2. Alternative general synthesis of macrocyclic esters

[0213] Alternatively, macrocyclic esters can be prepared as described in Scheme 2. An appropriately substituted and protected indolyl boronic ester (7) can be coupled in the presence of a Pd catalyst with (S)-2-amino-3-(4-bromothiazol-2-yl)propanoic acid. Petition 870250108725, dated 11 / 27 / 2025, pp. 254 / 351 74 / 165 followed by iodination, deprotection, and ester hydrolysis. Subsequent coupling with methyl(S)-hexahydropyridazine-3-carboxylate, followed by hydrolysis and macrolactonization, can result in an iodo intermediate (11). Subsequent palladium-mediated borylation and coupling in the presence of a Pd catalyst with an appropriately substituted iodoaryl or iodoheteroaryl intermediate can produce an appropriately protected macrocyclic intermediate. Alkylation, deprotection, and coupling with an appropriately substituted carboxylic acid (or other coupling partner) result in a macrocyclic product. Additional deprotection or functionalization steps might be required to produce a final compound 6.

[0214] Furthermore, with respect to Scheme 2, the thiazole may be replaced by an alternative optionally substituted 5- to 6-membered heteroarylene, or an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene (e.g., morpholino), or optionally substituted 6-membered arylene (e.g., phenyl).

[0215] Compounds in Table 1 in this document were prepared using methods disclosed herein or were prepared using methods described herein combined with the knowledge of someone skilled in the art.

[0216] As described herein, the GTP hydrolysis-promoting compound RAS(ON) increases the rate of RAS GTP (guanosine triphosphate) hydrolysis relative to the rate of RAS GTP hydrolysis in the absence of the compound. GTP hydrolysis refers to the process by which a GTP molecule is cleaved into GDP (guanosine diphosphate) and inorganic phosphate (Pi) in the presence of water. In various embodiments, the rate of GTP hydrolysis is increased by about 5-100% (e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%, or about 100%, Petition 870250108725, dated 11 / 27 / 2025, pp. 255 / 351 75 / 165 including all values ​​and intervals between these values), 10-95%, 15-90%, 20-85%, 25-75%, 30-70%, 35-65%, 40-60%, 45-55%, or 50% compared to the GTP hydrolysis rate in the absence of the compound. In various embodiments, the GTP hydrolysis rate is increased by about 2-100 times (e.g., at least about 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 times, including all values ​​and intervals between these values) compared to the GTP hydrolysis rate in the absence of the inhibitor.

[0217] Assays for measuring the rate of GTP hydrolysis are known in the art and contemplated herein. For example, the analysis of the GTP hydrolysis rate can be performed in cell culture or in a cell-free system. Thin-layer chromatography (TLC) is a technique used to separate and visualize different molecules, including nucleotides such as GTP and GDP. In a typical GTP hydrolysis assay, the reaction mixture containing GTP, RAS, and with or without a GTP hydrolysis-promoting compound RAS(ON) is incubated for a sufficient time and under suitable conditions. The reaction is then stopped, and the reaction products (GDP and Pi) can be separated by TLC and quantified. Colorimetric assays can be used that are based on the detection of a colored product generated by the reaction between Pi and a specific reagent, such as molybdate or malachite green.In this type of assay, the GTP hydrolysis reaction is carried out in the presence of a colorimetric reagent, and the absorbance of the colored product is measured over time. Fluorescence-based assays can also be used, including fluorescent nucleotides such as mant-GTP, which emit fluorescence after hydrolysis. The reaction mixture containing the fluorescent nucleotide and RAS, with or without a GTP hydrolysis-promoting compound RAS(ON), and the decrease in fluorescence over time are monitored using a fluorescence spectrophotometer. Radioactive assays can also be used with GTP. Petition 870250108725, dated 11 / 27 / 2025, pp. 256 / 351 76 / 165 radiolabeled ([y-32P]GTP or [a-32P]GTP), which allows highly sensitive detection of reaction products (GDP and Pi) by scintillation counting. Additional methods are described here, for example, in the examples below.

[0218] In some embodiments, hydrolysis is enhanced in the presence of a GTP hydrolysis-promoting compound RAS(ON) for a RAS protein that includes a G12C amino acid substitution relative to wild-type RAS or other RAS mutants. In some embodiments, GTP hydrolysis is enhanced for RAS that includes a G12D amino acid substitution relative to wild-type RAS or other KRAS mutants. In some embodiments, GTP hydrolysis is enhanced for RAS that includes a G12V amino acid substitution relative to wild-type RAS or other RAS mutants. In some embodiments, GTP hydrolysis is enhanced for RAS that includes a G13D amino acid substitution relative to wild-type RAS or other RAS mutants. In each of the above embodiments, the RAS does not have a mutation at residue 61 relative to wild-type RAS. b) RAS(OFF) inhibitors and RAS(OFF) degraders

[0219] The compositions described herein may include one or more RAS(OFF) inhibitors. Numerous selective mutant and pan-RAS inhibitors have been disclosed. A RAS(OFF) inhibitor may be administered or formulated in combination with a RAS(ON) GTP hydrolysis-promoting compound described herein. RAS(OFF) inhibitors are designed to inhibit RAS activity by targeting different regions of the RAS protein in its inactive state, preventing its activation and subsequent signaling.

[0220] In some embodiments, a RAS(OFF) inhibitor is a KRAS(OFF) inhibitor that has 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 Petition 870250108725, dated 11 / 27 / 2025, pp. 257 / 351 The 77 / 165 KRAS(OFF) inhibitor is specific for a KRASG12C mutation. KRASG12C(OFF) inhibitors use a covalent linking group that allows them to selectively target the mutant KRASG12C protein, and many of these inhibitors comprise a pyhmidine core. All KRASG12C(OFF) inhibitors target the same cysteine ​​residue in the mutant KRASG12C protein, leading to a conformational change that locks the protein into an inactive state. KRASG12C(OFF) inhibitors include, for example, AMG510 (sotorasib), MRTX849 (adagrasib), MRTX1257, GDC-6036 (divarasib), JDQ443 (opnurasib), ERAS-3490, LY3537982 (olomorasib), BI 1823911, BPI-421286, JAB-3312, JAB-21000, JAB-21822 (glecirasib), D-1553, D3S-001, HBI-2438, HS-10370, MK-1084, YL-15293, BBO-8520 (ON / OFF inhibitor), FMC-376 (ON / OFF inhibitor), GEC255 and GFH925 (IBI351). In some embodiments, the KRAS(OFF) inhibitor is selected from AMG 510 and MRTX849. In some embodiments, the KRAS(OFF) inhibitor is AMG 510. In some embodiments, the KRAS(OFF) inhibitor is selected from BPI 421286, JNJ-74699157 (ARS-3248), LY3537982, MRTX1257, ARS853, ARS1620, and GDC-6036. AMG 510: MRTX849: MRTX1257: ARS-1620:

[0221] In some embodiments, a KRAS(OFF) inhibitor is specific for a KRASG12D mutation. Many KRASG12D(OFF) inhibitors have been developed using G12C RAS(OFF) inhibitors as a starting point, thus sharing the structure of G12C inhibitors in combination with other chemical moieties, such as piperazine-based compounds. Non-limiting examples of KRASG12D(OFF) inhibitors include MRTX1133, MRTX282, JAB-22000, ERAS-4, ERAS-5024, HRS-4642, BI-2852, Petition 870250108725, dated 11 / 27 / 2025, pp. 258 / 351 78 / 165 ASP3082, TH-Z827, TH-Z835, QTX-3046, FGH375 (VS-7375), INCB161734 and KD-8. In some modes, the KRAS(OFF) inhibitor is MRTX1133.

[0222] Reference to “MRTX1133”, “TH-Z827”, “TH-Z835” and “KD-8” here means the following compounds: MRTX1133

[0223] In some embodiments, the small molecule RAS(OFF) inhibitor is specific for a KRASG12V mutation. In some embodiments, the small molecule RAS(OFF) inhibitor is specific for a KRASG13D mutation. In some embodiments, the small molecule RAS(OFF) inhibitor is specific for a pan-RAS(OFF) inhibitor. In some embodiments, the reference to the term RAS(OFF) inhibitor includes any RAS(OFF) inhibitor disclosed in any of the following patent applications: WO 2024056063, WO 2024055112, WO 2024054926, WO 2024054647, WO 2024054625, WO 2024051763, WO 2024051721, WO 2024050742, WO 2024050640, WO 2024046406, WO 2024046370, WO 2024045066, WO 2024044667, WO 2024044649, WO 2024044334, WO 2024041621, WO 2024041606, WO 2024041589, WO 2024041573 WO 2024040131, WO 2024040109, WO 2024040080, WO 2024036270, WO 2024034657, WO 2024034593, WO 2024034591, WO 2024034123, WO 2024032747, WO 2024032704, WO 2024032703, WO 2024032702, WO 2024031088, WO 2024030647, WO 2024030633, WO 2024029613, WO 2024022507, WO 2024022444, WO 2024020159, WO 2024019103, WO 2024017859, WO 2024017392, WO 2024015731, WO 2024015262, WO 2024012456, WO 2024009191, WO 2024008179, WO 2024008178, WO 2024008068, WO Petição 870250108725, de 27 / 11 / 2025, pág. 259 / 351 79 / 165 2024006445, WO 2024006424, WO 2024002373, WO 2023287896, WO 2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO 2023283213, WO 2023280280, WO 2023280136, WO 2023280026, WO 2023278600, WO 2023274383, WO 2023327324, WO 2023246914, WO 2023246903, WO 2023246777 WO 2023244713, WO 2023244615, WO 2023244604, WO 2023244600, WO 2023244599, WO 2023230190, WO 2023226630, WO 2023225302, WO 2023225252, WO 2023220421, WO 2023219941, WO 2023217148, WO 2023215802, WO 2023215801, WO 2023213269, WO 2023212548, WO 2023208005, WO 2023205719, WO 2023199180, WO 2023198191, WO 2023197984, WO 2023190748, WO 2023185864, WO 2023183755, WO 2023183585, WO 2023179703, WO 2023179629, WO 2023173017, WO 2023173016, WO 2023173014, WO 2023172737, WO 2023171781, WO 2023159087, WO 2023159086, WO 2023154766, WO 2023152255, WO 2023151674, WO 2023151621, WO 2023150394, WO 2023150284, WO 2023143623, WO 2023143605, WO 2023143352, WO 2023143352, WO 2023143312, WO 2023141570, WO 2023141300, WO 2023138662,WO 2023138601, WO 2023138589, WO 2023138524, WO 2023133183, WO 2023133181, WO 2023130012, WO 2023125989, WO 2023125627, WO 2023122662, WO 2023122154, WO 2023120742, WO 2023119677, WO 2023117681, WO 2023116934, WO 2023116895, WO 2023114733, WO 2023105491, WO 2023104018, WO 2023103906, WO 2023103523, WO 2023101928, WO 2023099624, WO 2023099624, WO 2023099620, WO 2023099612, WO 2023099608, WO 2023099592, WO 2023098832, WO 2023098425, WO 2023097227, WO 2023081840, WO 2023081476, WO 2023078424, WO 2023077441, WO 2023072297, WO 2023072188, WO 2023066371, WO 2023064857, WO 2023061463, WO 2023061294, WO 2023057985, WO 2023056951, WO 2023056421, WO 2023051586, WO 2023049697, WO, Petição 870250108725, de 27 / 11 / 2025, pág. 260 / 351 80 / 165 2023046135, WO 2023045960, WO 2023041059, WO 2023041059, WO 2023040989, WO 2023040513, WO 2023039240, WO 2023039020, WO 2023036282, WO 2023034290, WO 2023030517, WO 2023030495, WO 2023030385, WO 2023025116, WO 2023020523, WO 2023020521, WO 2023020519, WO 2023020518, WO 2023020347, WO 2023018812, WO 2023018810, WO 2023018809, WO 2023018699, WO 2023014979, WO 2023014006, WO 2023004102, WO 2023003417, WO 2023001141, WO 2023001123, WO 2022271658, WO 2022269508, WO 2022266167, WO 2022266069, WO 2022266015, WO 2022265974, WO 2022261154, WO 2022261154, WO 2022251576, WO 2022251296, WO 2022237815, WO 2022232332, WO 2022232331, WO 2022232320, WO 2022232318, WO 2022223037, WO 2022221739, WO 2022221528, WO 2022221386, WO 2022216762 (por exemplo, Composto 44 ou Composto 66a), WO 2022192794, WO 2022192790, WO 2022188729, WO 2022187411, WO 2022184178, WO 2022173870, WO 2022173678, WO 2022135346, WO 2022133731, WO 2022133038, WO 2022133345, WO 2022132200, WO 2022119748, WO 2022109485, WO 2022109487, WO 2022066805, WO 2022002102, WO 2022002018, WO 2021259331, WO 2021257828, WO 2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO 2021248082, WO 2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO 2021239058, WO 2021231526, WO 2021228161, WO 2021219090, WO 2021219090, WO 2021219072, WO 2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO 2021215544, WO 2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO 2021139678, WO 2021129824, WO Petição 870250108725, de 27 / 11 / 2025, pág. 261 / 351 81 / 165 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO 2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO 2021113595, WO 2021107160, WO 2021106231, WO 2021088458, WO 2021086833, WO 2021085653, WO 2021081212, WO 2021058018, WO 2021057832, WO 2021055728, WO 2021031952 WO 2021027911, WO 2021023247, WO 2020259513, WO 2020259432, WO 2020234103, WO 2020233592, WO 2020216190, WO 2020178282, WO 2020146613, WO 2020118066, WO 2020113071, WO 2020106647, WO 2020102730, WO 2020101736, WO 2020097537, WO 2020086739, WO 2020081282, WO 2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO 2018218071, WO 2018218069, WO 2018217651, WO 2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO 2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO 2018068017,WO 2018064510, WO 2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659, WO 2013155223, CN, 117683051, CN 117645627, CN 117624194, CN 117624190, CN 117586280, CN 117486901, CN 117466917, CN 117462688, CN 117362315,CN 117327102, CN 117327094, CN 117327074, CN 117285590, CN 117263959, CN 117247382, CN 117186095, CN 117164605, CN 116969977,CN 116925075, CN 116891489, CN 116731045, CN 116731044, CN 116554208, CN 116514846, CN 116478184, CN 116478141, CN 116410145,CN Petition 870250108725, dated 27 / 11 / 2025, p. 262 / 351 82 / 165 116375742, CN 116354988, CN 116332948, CN 116332938, CN 116327956, CN 116262759, CN 116217592, CN 116199703, NC 116162099, CN 116143806, CN 116143805, CN 116120315, CN 116102559, CN 115960105, CN 115894520, CN 115872979, CN 115850267, CN 115785199, CN 115785124, CN 115785124, CN 115724842, CN 115716840, CN 115703775, CN 115611923, CN 115611898, CN 115583937, CN 115572278,CN 115557949, CN 115521312, CN 115504976, CN 115490709, CN 115466272, CN 115433183, CN 115433179, CN 115403575, CN 115385938,CN 115385937, CN 115385912, CN 115381786, CN 115368383, CN 115368382, CN 115368381, CN 115353506, CN 115322158, CN 115304623,CN 115304602, CN 115197245, CN 115181106, CN 114989195, CN 114989166, CN 114989147, CN 114920741, CN 114920739, CN 114907387,CN 114874234, CN 114874201, CN 114716436, CN 114716435, CN 114685532, CN 114685460, CN 114591319, CN 114539293, CN 114539286,CN 114539246, CN114437107, CN114437084, CN114409653, CN114380827, CN114195804, CN114195788, CN114057776, CN114057744,CN 114057743, CN 113999226, CN 113980032, CN 113980014, CN 113929676, CN 113754653, CN 113683616, CN 113563323, CN 113527299,CN 113527294, CN 113527293, CN 113493440, CN 113429405, CN 113248521, CN 113087700, CN 113024544, CN 113004269, CN 112920183,CN 112778284, CN 112390818, CN 112390788, CN 112300196, CN 112300194, CN 112300173, CN 112225734, CN 112142735, CN 112110918,CN 112094269, CN 112047937, and CN 109574871, each of which is incorporated herein by reference in its entirety, including the composite structures disclosed therein.

[0224] In some embodiments, the RAS(OFF) inhibitor is a peptide-based inhibitor. Peptide-based RAS(OFF) inhibitors have been developed to target specific regions of the RAS protein, such as the region Petition 870250108725, dated 11 / 27 / 2025, pp. 263 / 351 83 / 165 Switch II 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, disrupting its interaction with its downstream effectors or other signaling proteins. These inhibitors are typically designed to mimic the binding motifs of proteins that interact with RAS 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 prevent the activation of downstream signaling pathways.

[0225] Peptide-based RAS(OFF) inhibitors can be classified into two main categories: those that target the RAS-effector interface and those that target other regions of the RAS protein. Peptide-based inhibitors that target the RAS-effector interface are designed to bind to the exchange regions of RAS that are critical for its interaction with downstream effectors such as RAF or PI3K. These inhibitors typically contain amino acid residues similar to those found in the binding motifs of proteins or effectors that interact with RAS and are generally designed to form hydrogen bonds or other interactions with key residues on the RAS surface.

[0226] Peptide-based RAS(OFF) inhibitors that target other regions of the RAS protein are typically designed to disrupt other interactions that are critical for RAS activation or signaling. For example, some peptide-based inhibitors are designed to bind to the hypervariable region of RAS, which is believed to play a role in membrane localization and protein anchoring. By binding to this region, peptide-based inhibitors can prevent proper localization of RAS in the plasma membrane, which is necessary for its Petition 870250108725, dated 11 / 27 / 2025, pp. 264 / 351 84 / 165 activation and signaling.

[0227] Several common motifs have been identified as important for the binding of proteins and effectors that interact with RAS and are frequently used in the design of peptide-based inhibitors. One example is the RAF-binding domain (RBD), which is found in many proteins that interact with RAS and is important for the interaction of RAS with downstream effectors such as RAF. The RBD contains a conserved amino acid sequence (Arg-Xaa-Arg) that is critical for RAS binding, and this motif has been incorporated into several peptide-based inhibitors designed to disrupt the RAS-RAF interaction. Another example is the PI3K RAS-binding domain (RBD), which is important for the interaction of RAS with this downstream effector. The PI3K RBD contains several conserved amino acid residues (such as Arg-Arg-Trp) that are essential for RAS binding, and these motifs have been used in the design of peptide-based inhibitors that target the RAS-PI3K interaction.Other common motifs used in peptide-based RAS(OFF) inhibitors include the Ras-binding domain (RBD) of other RAS-interacting proteins, such as RalGDS and SOS, as well as sequences that mimic the structure of the exchange regions of RAS itself. These motifs are typically used to optimize the binding affinity and selectivity of the inhibitor for the desired target protein or interaction.

[0228] In some embodiments, the RAS(OFF) inhibitor is an antibody or antigen-binding peptide specific for RAS(OFF). 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 example, some antibodies have been developed that target the switch regions of RAS proteins, which are essential for the activation of these proteins and their interaction with subsequent effectors. The binding of these antibodies to the switch regions can prevent the changes Petition 870250108725, dated 11 / 27 / 2025, pp. 265 / 351 85 / 165 conformational changes are necessary for RAS activation and subsequent signaling. Another approach involves the use of antibodies that target proteins that interact with RAS or subsequent effectors, such as RAF or PI3K. The binding of these antibodies to their target proteins can disrupt RAS-dependent signaling pathways and inhibit the growth and survival of cancer cells. In addition, some antibodies have been developed that can induce the internalization and degradation of RAS proteins, leading to their depletion and inhibition of subsequent signaling. For example, some antibodies have been developed that recognize the unique structure of mutant RAS proteins and direct them for degradation via the ubiquitin-proteasome pathway. Non-limiting 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).

[0229] In any modality that employs an inhibitor of RAS(OFF) here, a RAS(OFF) degrader targeting the OFF state of RAS can be used alternatively. Such degraders are known in the art. RAS degraders can be found, for example, in one or more of the following applications: WO 2024055112, WO 2024054625, WO 2024050742, WO 2024044334, WO 2024040080, WO 2024034657, WO 2024034593, WO 2024034591, WO 2024034123, WO 2024029613, WO 2024020159, WO 2024019103, WO 2024017392, WO 2023185864, WO 2023171781, WO 2023141570, WO 2023138524, WO 2023130012, WO 2023116934, WO 2023099620, WO 2023081476, WO 2023077441, and CN 115785199, each of which is incorporated herein by reference in its entirety, including the composite structures disclosed herein which are specifically incorporated herein by reference. The RAS(OFF) inhibitor structures disclosed herein provide a means to inhibit RAS(OFF). c) RTK inhibitors

[0230] The compositions and methods described herein may include a Petition 870250108725, dated 11 / 27 / 2025, pp. 266 / 351 86 / 165 GTP hydrolysis-promoting compound RAS(ON) in combination with one or more receptor tyrosine kinase inhibitors. A receptor tyrosine kinase (RTK) inhibitor is a type of molecule (e.g., small molecule, antibody, and nucleic acid) that binds to and blocks the activity of receptor tyrosine kinases or their ligands. RTKs are proteins found on the surface of cells that play a critical role in cell signaling and growth and have been developed as therapeutics for a range of diseases, including cancer, diabetes, and autoimmune diseases. i) EGFR inhibitors

[0231] In some embodiments, compositions and methods described herein may include one or more EGFR inhibitors. An EGFR inhibitor may be administered or formulated in combination with a RAS(ON) GTP hydrolysis-promoting compound and / or any additional therapeutic agent described herein. EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77: 639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):193540; and Yang et al., Cancer Res. 1999, 59:1236-1243. The EGFR inhibitor may be the monoclonal antibody Mab E7.6.3 (Yang, 1999 supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the same binding specificity. Petition 870250108725, dated 11 / 27 / 2025, pp. 267 / 351 87 / 165

[0232] Small molecule EGFR antagonists include gefitinib (Iressa®), lazertinib, erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):5658; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some modalities, the EGFR inhibitor is osimertinib (Tagrisso®). In some modalities, an EGFR inhibitor is one or more of the following: cetuximab, gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif). Additional, but not 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. An EGFR inhibitor may be ERAS-801. In some embodiments, an EGFR inhibitor is an ERBB inhibitor.In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3) and HER (ERBB4). In some embodiments, reference to the term EGFR inhibitor includes any disclosed EGFR inhibitor. em any two of the following patent applications : WO 2023041071, WO 2023049312, WO 2023020600, WO 2023284747, WO 2022206797, WO 2022258977, WO 2022033416, WO 2022033410, WO 2022105908, WO 2022100641, WO 2022014639, WO 2022007841, WO 2021018009, WO 2021057882, WO 2021252661, WO 2021018003, YOU 2021073498, YOU 2021238827, YOU 2020254547, YOU 2020216371, YOU 2020147838, YOU 2020207483, YOU 2020254572, YOU 2020001350, YOU 2021001351, YOU 2019164948, YOU 2019218958, YOU 2019046775, YOU 2019015655, YOU 2018121758, YOU 2018218963, YOU 2017220007, 2017205459, 2017161937, 2016192609, 199633980, 199630347, 2017161937, 2016192609, 199633980, 199630347, 2017161937, 2016192609, 199633980, 199630347, 2016192609; 199730034, YOU 199730044, YOU 199738994, YOU 199749688, YOU 199802434, TO 199738983, TO 199519774, TO 199519970, TO 199713771, TO Petition 870250108725, dated 11 / 27 / 2025, pp. 268 / 351 88 / 165 199802437, WO 199802438, WO 199732881, WO 199833798, WO 199732880, WO 199732880, WO 199702266, WO 199727199, WO 199807726, WO 1997 / 34895, WO 199631510, WO 199814449, WO 199814450, WO 199814451, WO 199509847, WO 199719065, WO 199817662, WO 199935146, WO 199935132, WO 199907701, WO 199220642, DE 19629652, EP 682027, EP 837063, EP 0787772, EP 0520722, EP 0566226, CN 115960018, CN 110283162, CN 114044774, CN111973601, CN 111973602 and CN113896744, each of which is incorporated herein by reference in its entirety, including the composite structures disclosed therein which are specifically incorporated herein by reference. ii) HER2 inhibitors

[0233] In some embodiments, compositions and methods described herein may include one or more HER2 inhibitors. A HER2 inhibitor may be administered or formulated in combination with a GTP hydrolysis-promoting compound RAS(ON) and / or any additional therapeutic agent described herein. In some embodiments, a HER2 inhibitor is one or more of the following: tucatinib, rastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), ado-trastuzumab emtansine (Kadcyla), and neratinib (Nerlynx). Non-limiting examples of HER2 inhibitors include monoclonal antibodies, such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS599626, HKI-357, BIBW 2992, ARRY-334543 and JNJ-26483327.In some embodiments, the reference to the term HER2 inhibitor includes any HER2 inhibitor disclosed in any of the following patent applications: WO 2021156178, WO 2021156180, WO 2021213800, WO 2021088987, WO 2013561183 and WO 2013056108, each of which is incorporated herein by. Petition 870250108725, dated 11 / 27 / 2025, pp. 269 / 351 89 / 165 reference in its entirety, including the composite structures disclosed therein which are specifically incorporated herein by reference. iii) MET inhibitors

[0234] In some embodiments, compositions and methods described herein may include one or more MET inhibitors. A MET inhibitor may be administered or formulated in combination with a GTP hydrolysis-promoting compound RAS(ON) and / or any additional therapeutic agent described herein. In some embodiments, a MET inhibitor is one or more of the following: Crizotinib (Xalkori), Cabozantinib (Cometriq, Cabometyx), Capmatinib (Tabrecta), Tepotinib (Tepmetko), Savolitinib (Volitinib), Onartuzumab (MetMab), Foretitinib (GSK1363089), MGCD-265 (Amuvatinib), SU11274 and SU5416. In some embodiments, the reference to the term MET inhibitor includes any MET inhibitor disclosed in any of the following patent applications: WO 2022226168, WO 2021222045, WO 2020047184, WO 2020015744, WO 2020244654, WO 2020156453, WO 2019206268, WO 2018077227, WO 2017012539, WO 2016015653, WO 2016012963, WO 2012015677, WO 2011162835, WO 2010089507, WO 2009091374, WO 2009056692, WO 2008051547, WO 2007130468, US 2012237524, CN 103497177, CN 107311983, CN 107382968, CN 110218191 and TW201331206, each of which is incorporated herein by reference in its entirety, including the composite structures disclosed therein which are specifically incorporated herein by reference. iv) AXL inhibitors

[0235] In some embodiments, compositions and methods described herein may include one or more AXL inhibitors. An AXL inhibitor may be administered or formulated in combination with a GTP hydrolysis-promoting compound RAS(ON) and / or any additional therapeutic agent described herein. AXL is a receptor tyrosine kinase belonging to the receptor family. Petition 870250108725, dated 11 / 27 / 2025, pp. 270 / 351 90 / 165 TAM, which also includes TYRO3 and MERTK. In some embodiments, an AXL inhibitor is one or more of the following: bemcentib, BGB324, R428, SGI 7079, TP-0903, BMS-777607, UNC2025 and TP-0903. In some embodiments, the reference to the term AXL inhibitor includes any disclosed AXL inhibitor. in any of the following patent applications: WO 2023045816, WO 2022237843, WO 2022246179, WO 2021012717, WO 2021088787, WO 2021067772, WO 2021239133, WO 2021204713, WO 2020238802, WO 2019039525, WO 2019101178, WO 2019074116, WO 2017146236, WO 2016097918, WO 2015012298, WO 2010005876, WO 2010083465, CN 115073367 and JP 2022171109, each of which is incorporated herein by reference in its entirety, including the composite structures disclosed therein which are specifically incorporated herein by reference. V) IGFR inhibitors

[0236] In some embodiments, compositions and methods described herein may include one or more inhibitors of insulin-like growth factor receptor 1 (IGF-1R). An IGFR inhibitor may be administered or formulated in combination with a GTP hydrolysis-promoting compound. RAS(ON) and / or any additional therapeutic agent described herein. Inhibitors of IGFR inhibitors were developed to target the IGFR receptor, which plays a critical role in cancer progression and metastasis. In some embodiments, an IGFR inhibitor is one or more of the following: linsitinib, AXL1717, OSI-906 (Linsitinib), BMS-754807, BI 836845, AZ12253801, PQIP (Pyrrolo[1,2-alquinoxaline]), and NVP-AEW541. In some embodiments, the reference to the term IGFR inhibitor includes any IGFR inhibitor disclosed in any of the following patent applications: WO 2022115946, WO 2022217923, WO 2021203861, WO 2021246413, WO 2020116398, WO 2019046600, WO 2018195250, WO 2018221521, 2018204872, WO 2017072196, WO 2016173682, WO 2015162291, 2015162292, WO 2010066868, WO 2006069202 and CN 112125916, each WO WO of Petition 870250108725, dated 11 / 27 / 2025, pp. 271 / 351 91 / 165 which is incorporated herein by reference in its entirety, including the composite structures disclosed herein which are specifically incorporated herein by reference. v) RET inhibitors

[0237] In some embodiments, compositions and methods described herein may include one or more transfection-rearranged inhibitors (RETs). A RET inhibitor may be administered or formulated in combination with a GTP hydrolysis-promoting compound RAS(ON) and / or any additional therapeutic agent described herein. RET plays a critical role in several cellular processes, including cell growth, differentiation, survival, and migration. RET is activated by the binding of its ligands, such as ligands of the glial cell lineage-derived neurotrophic factor (GDNF) family, leading to the activation of subsequent signaling pathways that promote these cellular processes. In some embodiments, a RET inhibitor is one or more of the following: pralsetinib, selpercatinib (LOXO-292), BLU-667, RXDX-105, TPX-0046, GSK3179106, molidustate (BAY 85-3934) and RPI-1 (Retrofina). In some embodiments, the reference to the term RET inhibitor includes any RET inhibitor disclosed in any of the following patent applications: WO 2021211380, WO 2021057963, WO 2021043209, WO 2021222017, WO 2020035065, WO 2020114487, WO 2020200314, WO 2020200316, WO 2020114494, WO 2018071447, WO 2018213329, WO 2017079140, WO 2014050781, CN 113943285, CN 113683610, CN 113683611, CN 113620944, CN 113620945, CN 113527291, CN 113527292, CN 113527290, CN 113135896, CN 111057075, CN111233899 and CN111362923, each of which is incorporated herein by reference in its entirety, including the composite structures disclosed therein which are specifically incorporated herein by reference. vi) ROS1 inhibitors

[0238] In some forms, the methods of composition Petition 870250108725, dated 11 / 27 / 2025, pp. 272 / 351 92 / 165 described herein may include one or more c-ros 1 (ROS1) oncogene inhibitors. A ROS1 inhibitor may be administered or formulated in combination with the GTP hydrolysis-promoting compound RAS(ON) and / or any additional therapeutic agent described herein. ROS1 is a receptor tyrosine kinase belonging to the insulin receptor family and plays a role in various cellular processes, including cell growth, differentiation, survival, and migration. In some embodiments, a ROS1 inhibitor is one or more of the following: taletrectinib, DS-6051b, TPX-0131, GZD824, and PF-06463922. In some embodiments, the reference to the term ROS1 inhibitor includes any ROS1 inhibitor disclosed in any of the following patent applications: WO 2021098703, WO 2020024825, and US 2017079972, each of which is incorporated herein by reference in its entirety, including the composite structures disclosed therein that are specifically incorporated herein by reference. vii) PDGFR inhibitors

[0239] In some embodiments, compositions and methods described herein may include one or more platelet-derived growth factor receptor (PDGFR) inhibitors. A PDGFR inhibitor may be administered or formulated in combination with the GTP hydrolysis-promoting compound RAS(ON) and / or any additional therapeutic agent described herein. PDGFR is a family of tyrosine kinase receptors consisting of two members, PDGFRa and PDGFRe. They are activated by binding to their ligands, such as platelet-derived growth factor (PDGF), leading to the activation of downstream signaling pathways that promote cell growth, proliferation, and survival. In some embodiments, a PDGFR inhibitor is one or more of the following: CP-673451, imatinib, nintedanib (ofev), sunitinib (sutent), pazopanib (votrient), regorafenib (stivarga), and dasatinib (sprycel). Petition 870250108725, dated 11 / 27 / 2025, pp. 273 / 351 93 / 165 viii) FGFR inhibitors

[0240] In some embodiments, compositions and methods described herein may include one or more fibroblast growth factor receptor (FGFR) inhibitors. An FGFR inhibitor may be administered or formulated in combination with the GTP hydrolysis-promoting compound RAS(ON) and / or any additional therapeutic agent described herein. FGFRs are a family of receptor tyrosine kinases consisting of four members, FGFR1-4. FGFRs are activated by binding to their ligands, fibroblast growth factors (FGFs), leading to the activation of subsequent signaling pathways that promote cell growth, differentiation, and survival. In some embodiments, the FGFR inhibitor is an FGFR2 inhibitor. In some embodiments, the FGFR inhibitor is an FGFR4 inhibitor. In some modalities, an FGFR inhibitor is one or more of the following: futibatinib (TAK-659), erdafitinib (Balversa), infigratinib (Truseltiq), Debio 1347, and rogaratinib (BAY 1163877).In some embodiments, the reference to the term FGFR inhibitor includes any FGFR inhibitor disclosed in any of the following patent applications: WO 2022033472, WO 2022152274, WO 2022166469, WO 2022206939, WO 2021037219, WO 2021089005, WO. 2021113462, WO 2020185532, WO 2019213544, WO 2020164603, WO 2019154364, WO 2019034076, WO 2019213506, WO 2019223766, WO 2018028438, WO 2018153373, WO 2018121650, WO 2018010514, WO 2017028816, WO 2017118438, WO 2016134320, WO 2015008844, WO 2014172644, WO 2014007951, WO 2013179033, WO 2013087578, WO 2012047699, CN 105906630, CN 115869315, CN 115141176, CN 115043832 and CN 115028634, each of which is incorporated herein by reference in its entirety, including the composite structures disclosed therein which are specifically incorporated herein by reference. ix) VEGF inhibitors

[0241] In some modalities, compositions and methods here Petition 870250108725, dated 11 / 27 / 2025, pp. 274 / 351 94 / 165 described may include one or more vascular endothelial growth factor (VEGF) signaling inhibitors. VEGF (vascular endothelial growth factor) signaling inhibitors are a class of drugs that target the VEGF-mediated signaling pathway and its receptors. VEGF plays a key 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 therapy. A VEGF inhibitor may be administered or formulated in combination with the GTP hydrolysis-promoting compound RAS(ON) and / or any additional therapeutic agent described herein.In some embodiments, the VEGF inhibitor is an antibody or antigen-binding regions that bind specifically to VEGF (e.g., bevacizumab), or soluble VEGF receptors or a ligand-binding region for these, such as VEGFTRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that bind specifically to them). In some embodiments, the VEGF inhibitor is one or more of the following: bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, and pazopanib. d) SHP inhibitors

[0242] In some embodiments, the compositions and methods described herein may include one or more SHP inhibitors. An SHP inhibitor may be administered or formulated in combination with a GTP hydrolysis-promoting compound RAS(ON) and / or any additional therapeutic agent described herein. In some embodiments, the SHP inhibitor is an SHP1 inhibitor. In some embodiments, the SHP inhibitor is an SHP2 inhibitor. In some embodiments, the SHP1 inhibitor is SB6299, also known as DA-4511. In some embodiments, an SHP2 inhibitor is one or more of the following: SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, or BBP-398. In some embodiments, the Petition 870250108725, dated 11 / 27 / 2025, pp. 275 / 351 95 / 165 reference to the term SHP2 inhibitor includes any SHP2 inhibitor disclosed em qualquer um dos seguintes pedidos de patente: WO 2023282702, WO 2023280283, WO 2023280237, WO 2023018155, WO 2023011513, WO 2022271966, WO 2022271964, WO 2022271911, WO 2022259157, WO 2022242767, WO 2022241975, WO 2022237676, WO 2022237367, WO 2022237178, WO 2022235822, WO 20222084008, WO 2022135568, WO 2022063190, WO 2022043865, WO 2022042331, WO 2022033430, WO 2022017444, WO 2022007869, WO 2021259077, WO 2021249449, WO 2021249057, WO 2021244659, WO 2021218755, WO 2021176072, WO 2021171261, WO 2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO 2021143701, WO 2021143680, WO 2021281752, WO 2021121397, WO 2021119525, WO 2021115286, WO 2021110796, WO 2021088945, WO 2021073439, WO 2021061706, WO 2021061515, WO 2021043077, WO 2021033153, WO 2021028362, WO 2021033153, WO 2021028362, WO 2021018287, WO 2020259679, WO 2020249079, WO 2020210384, WO 2020201991, WO 2020181283, WO 2020177653, WO 2020165734, WO 2020165733, WO 2020165732, WO 2020156243, WO 2020156242, WO 2020108590,WO 2020104635, WO 2020094104, WO 2020094018, WO 2020081848, WO 2020073949, WO 2020073945, WO 2020072656, WO 2020065453, WO 2020065452, WO 2020063760, WO 2020061103, WO 2020061101, WO 2020033828, WO 2020033286, WO 2020022323, WO 2019233810, WO 2019213318, WO 2019183367, WO 2019183364, WO 2019182960, WO 2019167000, WO 2019165073, WO 2019158019, WO 2019152454, WO 2019051469, WO 2019051084, WO 2018218133, WO 2018172984, WO 2018160731, WO 2018136265, WO 2018136264, WO 2018130928, WO 2018129402, WO 2018081091, WO 2018057884, WO 2018013597, WO 2017216706, WO 2017211303, WO 2017210134, WO 2017156397, WO 2017100279, WO 2017079723, WO, Petição 870250108725, de 27 / 11 / 2025, pág. 276 / 351 96 / 165 2017078499, WO 2016203406, WO 2016203405, WO 2016203404, WO 2016196591, WO 2016191328, WO 2015107495, WO 2015107494,WO 2015107493, WO 2014176488, WO 2014113584, CN 115677661, CN 115677660, CN 115611869, CN 115521305, CN 115490697, CN 115466273, CN 115394612, CN 115304613, CN 115304612, CN 115300513,CN 115197225, CN 114957162, CN 114920759, CN 114716448, CN 114671879, CN 114539223, CN 114524772, CN 114213417, CN 114195799, CN 114163457, CN 113896710, CN 113248521, CN 113248449, CN 113135924, CN 113024508, CN 112920131, CN 112823796, CN 112409334,CN 112402385, CN 112174935, 111848599, CN 111704611, CN 111393459, CN 111265529, CN 110143949, CN 108113848, US 11179397, US 11044675, US 11034705, US 11033547, US 11001561, US 10988466, US 10954243, US 10934302 or US 10858359, each of which is incorporated herein by reference in its entirety, including the composite structures disclosed therein which are specifically incorporated herein by reference. e) SOS1 inhibitors

[0243] In some embodiments, compositions and methods described herein may include one or more SOS1 inhibitors. An SOS1 inhibitor may be administered or formulated in combination with the GTP hydrolysis-promoting compound RAS(ON) and / or any additional therapeutic agent described herein. In some embodiments, an SOS1 inhibitor is one or more of the following: RMC-5845, RMC-4948, RMC-0331, BI-1701963, BI-3406, SDR5, MRTX-0902 and BAY-293. In some embodiments, the reference to the term SOS1 inhibitor includes any SOS1 inhibitor disclosed in any of the following patent applications: WO 2023029833, WO 2023041049, WO 2023022497, WO 2022184116, WO 2022170952, WO 2022170917, WO 2022171184, WO 2022170802, WO 2022161461, WO 2022121813, WO 2022028506, WO 2022139304, WO 2021228028, WO 2019122129, CN Petition 870250108725, dated 11 / 27 / 2025, pp. 277 / 351 97 / 165 115215847, CN 115028644, CN 114685488, CN 111393519, each of which is incorporated herein by reference in its entirety, including the composite structures disclosed therein which are specifically incorporated herein by reference. f) Pharmaceutical Compositions

[0244] The disclosure provides pharmaceutical compositions including one or more RAS(ON) GTP hydrolysis-promoting compounds in combination with one or more RAS(OFF) inhibitors, or a pharmaceutically acceptable salt thereof, as active agents, and a pharmaceutically acceptable excipient.

[0245] In some embodiments, a compound is present in a pharmaceutical composition in a unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.In some embodiments, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for: oral administration, for example, solutions (aqueous or non-aqueous solutions or suspensions), tablets, for example, those intended for buccal, sublingual and / or systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, subcutaneous, intramuscular, intravenous or epidural injection, such as, for example, a sterile solution or suspension or sustained-release formulation; topical application, for example, in the form of a cream, ointment or controlled-release patch or a spray applied to the skin; intravaginal or intrarectal, for example, as a pessary, cream or foam; sublingual; ocular; transdermal; or on the nasal, pulmonary and / or other mucous surfaces. Petition 870250108725, dated 11 / 27 / 2025, pp. 278 / 351 98 / 165

[0246] The compounds described in this document, whether expressly stated or not, may be supplied or used in salt form, for example, a pharmaceutically acceptable salt form, unless expressly stated otherwise.

[0247] The compounds of the disclosure may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or the salts may, in the case of acidic forms of the compounds of the disclosure, 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, such as hydrochloric, sulfuric, hydrobromic, acetic, lactic, citric, or tartaric acids to form acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like to form basic salts. The methods for preparing the appropriate salts are well established in the art.

[0248] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, iodide, optionally substituted 2-hydroxyl ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, Petition 870250108725, dated 11 / 27 / 2025, pp. 279 / 351 99 / 165 undecanoate, valerate salts and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0249] For use as treatment of individuals, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, may be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration and the type of treatment desired, for example, prevention, prophylaxis or therapy, the compounds, or a pharmaceutically acceptable salt thereof, are formulated in accordance with these parameters. A summary of such techniques may 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.

[0250] The compositions may be prepared according to conventional methods of mixing, granulation or coating, respectively, and the present pharmaceutical compositions may contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, by weight or volume. In some embodiments, the compounds, or a pharmaceutically acceptable salt thereof, described in this document may be present in amounts totaling 1-95% by weight of the total weight of a composition, such as a pharmaceutical composition.

[0251] The composition can be supplied in a form of Petition 870250108725, dated 11 / 27 / 2025, pp. 280 / 351 100 / 165 dosage that is suitable for intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, ​​intrathecal, epidural, aural or ocular administration, or by injection, inhalation or direct contact with the nasal, genitourinary, reproductive or oral mucosa. Thus, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels, including hydrogels, pastes, ointments, creams, plasters, salves, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic distribution or aerosols. The compositions may be formulated in accordance with conventional pharmaceutical practice.

[0252] Formulations may be prepared in a manner suitable for systemic administration or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. A formulation will generally include a diluent, as well as, in some cases, adjuvants, buffers, preservatives, and the like. The compounds, or a pharmaceutically acceptable salt thereof, may also be administered in liposomal compositions or as microemulsions.

[0253] For injection, formulations may be prepared in conventional forms, such as liquid solutions or suspensions, or as solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients include, for example, water, saline solution, dextrose, glycerol and the like. These compositions may also contain quantities of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents and the like, such as, for example, Petition 870250108725, dated 11 / 27 / 2025, pp. 281 / 351 101 / 165 for example, sodium acetate and sorbitan monolaurate, and so on.

[0254] Several sustained-release drug systems have also been devised. See, for example, US Patent No. 5,624,677.

[0255] Systemic administration may also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal distribution, and intranasal administration. Oral administration is also suitable for dissemination compounds, or pharmaceutically acceptable salts thereof. Suitable forms include syrups, capsules, and tablets, as understood in the art.

[0256] Each compound, or a pharmaceutically acceptable salt thereof, as described in this document, may be formulated in a variety of ways known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Other combination therapy modalities are described in this document.

[0257] Individually or separately formulated agents may be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and a powder, one suppository and a liquid in one vial, two topical creams, etc. The kit may include optional components that assist in administering the unit dose to subjects, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. In addition, the unit dose kit may contain instructions for the preparation and administration of the compositions. The kit may be manufactured as a single-use unit dose for one subject, multiple uses for a specific subject (at a constant dose or where the individual compounds, or a pharmaceutically acceptable salt thereof, may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to Petition 870250108725, dated 11 / 27 / 2025, pp. 282 / 351 102 / 165 multiple subjects (bulk packaging). The kit components can be assembled into boxes, blister packs, bottles, tubes, and similar containers.

[0258] Oral formulations include tablets containing the active ingredients in a mixture with pharmaceutically acceptable, non-toxic excipients. These excipients may be, for example, inert diluents or bulking agents (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates or alginic acid);Binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, aluminum and magnesium silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricating, slip and anti-adhesive agents (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils or talc). Other pharmaceutically acceptable excipients may include colorants, flavoring agents, plasticizers, humectants, buffering agents and the like.

[0259] Two or more compounds may be mixed in a tablet, capsule or other vehicle, or they may be partitioned. In one example, the first compound is contained inside the tablet and the second compound is outside, so that a substantial portion of the second compound is released before the release of the first compound.

[0260] Oral formulations may also be supplied as chewable tablets or as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., starch) Petition 870250108725, dated 11 / 27 / 2025, pp. 283 / 351 103 / 165 potato, 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 oil medium, for example, peanut oil, liquid paraffin or olive oil. Powders, granules and pellets can be prepared using the ingredients mentioned above in tablets and capsules in a conventional manner using, for example, a mixer, a fluid bed apparatus or a spray drying apparatus.

[0261] Controlled dissolution or release by diffusion may be achieved by appropriately coating a tablet, capsule, pellet or granulated formulation of compounds, or by incorporating the compound, or a pharmaceutically acceptable salt thereof, into an appropriate matrix. A controlled-release coating may include one or more of the coating substances mentioned above or, for example, shellac, beeswax, glycoceryl wax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, optionally substituted 2-hydroxymethacrylate, methacrylate hydrogels, 1,3-butylene glycol, ethylene glycol methacrylate or polyethylene glycols.In a controlled-release matrix formulation, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbon.

[0262] The liquid forms in which the compounds, or a pharmaceutically acceptable salt thereof, and the compositions of this disclosure may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous suspensions or Petition 870250108725, dated 11 / 27 / 2025, pp. 284 / 351 104 / 165 oily and flavored emulsions containing edible oils, such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0263] Generally, when administered to a human, the oral dosage of any of the disclosed compounds, or a pharmaceutically acceptable salt thereof, will depend upon the nature of the compound and may be readily determined by one skilled in the art. A dosage may be, for example, about 0.001 mg to about 2,000 mg per day, about 1 mg to about 1,000 mg per day, about 5 mg to about 500 mg per day, about 100 mg to about 1,500 mg per day, about 500 mg to about 1,500 mg per day, about 500 mg to about 2,000 mg per day, or any range derivable therefrom.

[0264] In some embodiments, the pharmaceutical composition may also include an additional compound with antiproliferative (e.g., anticancer) activity. Depending on the mode of administration, the compounds, or a pharmaceutically acceptable salt thereof, will be formulated in compositions suitable for easy distribution. Each compound, or a pharmaceutically acceptable salt thereof, of a combination therapy may be formulated in a variety of ways known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Preferably, the first and second agents are formulated together for simultaneous or near-simultaneous administration of the agents.

[0265] It will be appreciated that the pharmaceutical compounds and compositions of this disclosure can be formulated and used in combination therapies, that is, the pharmaceutical compounds and compositions can be formulated or administered simultaneously with, before, or subsequent to, one or more other therapies or procedures. Petition 870250108725, dated 11 / 27 / 2025, pp. 285 / 351 105 / 165 desired physicians. The particular combination of therapies (therapeutics or procedures) to be employed in a combination regimen will take into account the compatibility of the desired therapies or procedures and the desired therapeutic effect to be achieved. It will also be appreciated whether the therapies employed can achieve a desired effect for the same disorder, or can achieve different effects (e.g., control of any adverse effects).

[0266] The administration of each drug in a combination therapy, as described in this document, may independently be from one to four times a day for one day to one year, and may even be for the subject's life. Long-term chronic administration may be indicated. II. Methods

[0267] In one aspect, the present disclosure is directed to methods of treating a disease or disorder that is characterized by aberrant RAS activity (e.g., cancer or a RASopathy). In some embodiments, the disease or disorder is cancer (e.g., a cancer with one or more RAS mutations that cause aberrant RAS activity). In the foregoing embodiment, the method generally comprises administering to the subject a therapeutically effective amount of a RAS(ON) GTP hydrolysis-promoting compound and a RAS(OFF) inhibitor. Suitable RAS(ON) GTP hydrolysis-promoting compounds and additional therapeutic agents useful in the methods disclosed herein are described in Section I and incorporated herein by reference.

[0268] Consequently, the disclosure provides methods of treating cancer in a subject in need thereof, the methods including administering to the subject a therapeutically effective amount of one or more GTP hydrolysis-promoting compounds RAS(ON) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. Petition 870250108725, dated 11 / 27 / 2025, pp. 286 / 351 106 / 165 including one or more GTP hydrolysis-promoting compounds RAS(ON) described herein or salts thereof.

[0269] The disclosure also provides a method of treating cancer in a subject in need thereof, wherein the cancer includes a mutation in RAS. In one embodiment, the addition of a RAS(ON) GTP hydrolysis-promoting compound, or a pharmaceutically acceptable salt or composition thereof, synergistically increases the activity of a RAS(OFF) inhibitor, or a pharmaceutically acceptable salt or composition thereof. Any method for determining whether two compounds exhibit synergy may be used to determine the synergistic effect of the combination, such as the methods described herein.

[0270] Several mathematical models have been developed to determine whether two compounds act synergistically, that is, 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 well-known models in the pharmaceutical industry and can be used to calculate a “synergy score” that indicates whether synergy has been detected and the magnitude of that synergy. Additional models for determining the synergy of two compounds can be found in the examples below.

[0271] In general, mathematical models use data obtained from individual agent values ​​to determine the predicted additive effect of the combination, which is compared to the observed effect for 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) with the predicted combination response (Yp), Petition 870250108725, dated 11 / 27 / 2025, pp. 287 / 351 107 / 165, which was obtained based on the assumption that there are no drug interaction effects. Typically, the effect of the combination is declared synergistic if Yo is greater than Yp.

[0272] In some embodiments, “synergistic effect” as used herein refers to the combination of a GTP hydrolysis-promoting compound RAS(ON) or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent (e.g., a RAS(OFF) inhibitor) or a pharmaceutically acceptable salt thereof producing an effect, for example, any of the beneficial or desired outcomes including in vitro results as well as clinical results or outcomes as described herein, that is greater than the sum of the effect observed when a GTP hydrolysis-promoting compound RAS(ON) or a pharmaceutically acceptable salt thereof and an additional therapeutic agent (e.g., a RAS(OFF) inhibitor) or a pharmaceutically acceptable salt thereof are administered alone. The greater the hydrolysis capacity of a GTP hydrolysis-promoting compound RAS(ON), the greater the synergistic effect observed with a RAS(OFF) inhibitor.

[0273] In some embodiments, the disclosure provides methods of treating cancer in a subject in need thereof, the methods including administering to the subject a therapeutically effective amount of one or more GTP hydrolysis-promoting compounds RAS(ON) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition and a receptor tyrosine kinase (RTK) inhibitor.

[0274] In some embodiments, the disclosure provides methods of treating cancer in a subject in need thereof, the methods including administering to the subject a therapeutically effective amount of one or more GTP hydrolysis-promoting compounds RAS(ON) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. Petition 870250108725, dated 11 / 27 / 2025, pp. 288 / 351 108 / 165 and an SHP2 inhibitor.

[0275] In some embodiments, the disclosure provides methods of treating cancer in a subject in need thereof, the methods including administering to the subject a therapeutically effective amount of one or more RAS(ON) GTP hydrolysis-promoting compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition and an SOS1 inhibitor.

[0276] The GTP hydrolysis promoter RAS(ON) and the additional therapeutic agent may be administered simultaneously or sequentially. The GTP hydrolysis promoter RAS(ON) and the RAS(OFF) inhibitor may be administered as a single formulation or in separate formulations. In some embodiments, the GTP hydrolysis promoter RAS(ON) is administered for a first time period; and the additional therapeutic agent is administered for a second time period, wherein the first time period and the second time period do not overlap and the first time period precedes the second time period; and the additional therapeutic agent and the GTP hydrolysis promoter RAS(ON) are administered for a second time period, wherein the first time period and the second time period do not overlap and the first time period precedes the second time period.

[0277] In some modalities, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendix cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some modalities, the cancer is of the appendix, endometrium, or Petition 870250108725, dated 11 / 27 / 2025, pp. 289 / 351 109 / 165 melanoma. In some forms, the cancer is non-small cell lung cancer. In certain forms, the cancer is pancreatic cancer.

[0278] In some embodiments, the compounds of this disclosure or pharmaceutically acceptable salts thereof, pharmaceutical compositions including such compounds or salts and methods provided herein may be used for the treatment of a wide variety of cancers, such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, pulmonary, oral, ovarian, prostate and thyroid carcinomas and sarcomas. Other types of cancer include, for example: Cardiac, for example: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung, for example: bronchial carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal tumors, for example: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, lipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract, for example: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver, for example: Petition 870250108725, dated 11 / 27 / 2025, pp. 290 / 351 110 / 165 Hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract, for example: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone, for example: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, chordoma of malignant giant cell tumor, osteochondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;Nervous system, for example: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), neurofibroma of the spinal cord, neurofibromatosis type 1, meningioma, glioma, sarcoma);Gynecological, for example: uterus (endometrial carcinoma, uterine carcinoma, endometrial carcinoma of the uterine body), cervix (cervical carcinoma, pre-tumoral cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematological, for example: blood (myeloid leukemia (acute and chronic), acute lymphoblastic myeloproliferative neoplasms), multiple myeloma, myelodysplastic syndrome), disease of Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);Skin, for example: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles, nevi; Petition 870250108725, dated 11 / 27 / 2025, pp. 291 / 351 111 / 165 dysplastic, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands, for example: neuroblastoma.

[0279] In some forms, the cancer includes a RAS mutation, such as a RAS mutation described here. In some forms, a mutation is selected from: the following KRAS mutants: 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 mutants: 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 mutants: G12D, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, A59D, E132K, E49K, T50I, A146V or A59T and combinations thereof; or a combination of any of the above. In some forms, the cancer includes a selected KRAS mutation from the group consisting of G12C, G12D, G13C, G12V, G13D, G12R, and G12S. In some forms, the cancer includes an NRAS mutation in G12C.In some forms, the cancer includes one RAS mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some forms, the cancer includes two RAS mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V.

[0280] In some embodiments, a compound of the present disclosure binds to or inhibits more than one RAS mutant. In some embodiments, a compound may inhibit both KRAS G12D and KRAS G12V. In some embodiments, a compound may bind to or inhibit both KRAS G12V and KRAS G12S. In some embodiments, a compound of the present disclosure binds to or inhibits wild-type RAS in addition to a RAS mutant. In some embodiments, a compound of the present disclosure binds to or inhibits RAS in addition to one or more additional RAS mutations (e.g., K-, H-, or N-RAS). Petition 870250108725, dated 11 / 27 / 2025, pp. 292 / 351 112 / 165 KRAS G12D, G12V, G12C, G13D, G12R, G12A, G12S, A146T, G13C, K117N, A146V, G12F, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V; K-, Hou N-RASamP 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 N-RASamp and NRAS (G12D, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, A59D, E132K, E49K, T50I, A146V or A59T).

[0281] In some forms, the cancer is non-small cell lung cancer, and the RAS mutation includes a KRAS mutation, such as KRAS G12C, KRAS G12V, or KRAS G12D. In some forms, the cancer is colorectal cancer, and the RAS mutation includes a KRAS mutation, such as KRAS G12C, KRAS G12V, or KRAS G12D. In some forms, the cancer is pancreatic cancer, and the RAS mutation includes an NRAS mutation, such as NRAS G12D. In some forms, the cancer is melanoma.

[0282] In some modalities, a cancer includes a RAS mutation and an STK11LoF, KEAP1, EPHA5, or NF1 mutation. In some modalities, the cancer is non-small cell lung cancer and includes a KRAS G12C mutation. In some modalities, the cancer is non-small cell lung cancer and includes a KRAS G12C mutation and an STK11LoF mutation. In some modalities, the cancer is non-small cell lung cancer and includes a KRAS G12C mutation and an STK11LoF mutation. In some modalities, a cancer includes a KRAS G13C RAS ​​mutation and an STK11LoF, KEAP1, EPHA5, or NF1 mutation. In some modalities, the cancer is non-small cell lung cancer and includes a KRAS G12D mutation. In some modalities, the cancer is non-small cell lung cancer and includes a KRAS G12V mutation. In some forms, the cancer is colorectal cancer and includes a KRAS G12C mutation. In some forms, the cancer is pancreatic cancer and includes a KRAS G12D mutation. Petition 870250108725, dated 11 / 27 / 2025, pp. 293 / 351 113 / 165 In some forms, the cancer is pancreatic cancer and includes a KRAS G12V mutation. In some forms, the cancer is pancreatic cancer and includes a KRAS G12R mutation. In some forms, the cancer is endometrial cancer and includes a KRAS G12C mutation. In some forms, the cancer is gastric cancer and includes a KRAS G12C mutation.

[0283] Methods for detecting a mutation in a KRAS, HRAS, or NRAS nucleotide sequence are known to experts in the field. These methods include, among others, restriction fragment length polymorphism assays by polymerase chain reaction (PCR-RFLP), single-strand conformation polymorphism assays by polymerase chain reaction (PCR-SSCP), real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification assays (MASA), direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution fusion assays, and microarray analyses. In some modalities, samples are evaluated for G12C KRAS, HRAS, or NRAS mutations by real-time PCR. In real-time PCR, fluorescent probes specific for the KRAS, HRAS, or NRAS G12C mutation are used.When a mutation is present, the probe binds and fluorescence is detected. In some modalities, the KRAS, HRAS, or NRAS G12C mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 or exon 3) in the KRAS, HRAS, or NRAS gene. This technique will identify all possible mutations in the sequenced region.

[0284] Methods for detecting a mutation in a KRAS, HRAS, or NRAS protein are known to experts in the field. These methods include, among others, the detection of a KRAS, HRAS, or NRAS mutant using a specific binding agent (e.g., an antibody) for Petition 870250108725, dated 11 / 27 / 2025, pp. 294 / 351 114 / 165 the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing. Other methods include ctDNA measurement (e.g., Cescon et al., Nature Cancer 1: 276-290 (2020)), and the use of a high-sensitivity diagnostic assay (with CEIVD labeling), for example, as described in Domagala, et al., Pol J Pathol 3: 145-164 (2012), incorporated here by reference in its entirety, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See also, for example, WO 2020 / 106640.

[0285] Methods for determining whether a tumor or cancer includes a G12C mutation or another KRAS, HRAS, or NRAS mutation may use a variety of samples. In some modalities, the sample is taken from a subject with a tumor or cancer. In some modalities, the sample is a fresh tumor / cancer sample. In some modalities, the sample is a frozen tumor / cancer sample. In some modalities, the sample is a (CTC) sample. In some modalities, the sample is processed into a cell lysate. In some modalities, the sample is processed into DNA or RNA.

[0286] Also provided is a method of inhibiting or binding to a RAS protein in a cell, the method including contacting the cell with an effective amount of a combination of a GTP hydrolysis-promoting compound RAS(ON) of the present disclosure, or a pharmaceutically acceptable salt thereof, and optionally an additional therapeutic agent (e.g., a RAS(OFF) inhibitor, RTK inhibitor, SHP2 inhibitor or SOS1 inhibitor), or a pharmaceutically acceptable salt thereof. The cell may be a cancer cell. The cancer cell may be of any type of cancer described herein. The cell may be in vivo or in vitro.

[0287] In some embodiments of any of the methods described herein, prior to treatment with the compositions or methods of the invention, the Petition 870250108725, dated 11 / 27 / 2025, pp. 295 / 351 115 / 165 patients were treated with one or more of the following: chemotherapy, a targeted anticancer agent, radiotherapy, and surgery, and optionally, prior treatment was unsuccessful; and / or the patient underwent surgery and, optionally, the surgery was unsuccessful; and / or the patient was treated with a platinum-based chemotherapeutic agent and, optionally, the patient was previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and / or the patient was treated with a kinase inhibitor and, optionally, prior treatment with the kinase inhibitor was unsuccessful; and / or the patient was treated with one or more other therapeutic agents.

[0288] In several embodiments, the disclosure provides a method of treating cancer in a subject comprising administering to the subject a GTP hydrolysis-promoting compound RAS(ON) or a combination with, optionally, an additional therapeutic agent (e.g., a RAS(OFF) inhibitor, an RTK inhibitor, an SHP2 inhibitor, or an SOS1 inhibitor) as described herein, wherein the subject has one or more tumors that are resistant to or unresponsive to treatment. In several embodiments, the subject has one or more tumors that are resistant to or unresponsive to one or more treatments selected from the group consisting of surgery, radiation, chemotherapy, biological agents, small molecules, cell-based therapy, hormone therapy, and immunotherapy. In several embodiments, the treatment is a standard of care therapy, first-line therapy, second-line therapy, or third-line therapy.In several modalities, the subject has one or more tumors that have progressed during one or more treatments, where the treatments are standard therapy, first-line therapy, second-line therapy, or third-line therapy.

[0289] First-line therapy is defined as treatment administered to a subject suffering from cancer who has not received any Petition 870250108725, dated 11 / 27 / 2025, pp. 296 / 351 116 / 165 prior treatment. Second-line therapy is defined as treatment administered to an individual suffering from cancer who has previously received first-line therapy but experienced disease progression during first-line treatment. Third-line therapy is defined as treatment administered to an individual suffering from cancer who has previously received first- and second-line treatment but experienced disease progression during second-line treatment. Each specific type of cancer has a first-, second-, and third-line therapy. First-, second-, and third-line therapies for cancer types are known in the art. Furthermore, FDA-approved drug labels will indicate whether a given drug is approved as a first-, second-, or third-line therapy.

[0290] Several criteria and definitions published in the literature can be used to determine the effect of one or more treatments on tumors in a subject suffering from cancer. Based on these criteria, tumors are defined as “responsive”, “stable” or “progressive” when they improve, remain the same or worsen during treatment, respectively.

[0291] Examples of commonly used criteria published in the literature include Response Evaluation Criteria in Solid Tumors (RECIST), Modified Response Evaluation Criteria in Solid Tumors (mRECIST), PET Response Criteria in Solid Tumors (PERCIST), Choi Criteria, Lugano Response Criteria, European Association for the Study of the Liver (EASL) Criteria, Response Evaluation Criteria in Liver Cancer (RECICL), and WHO Criteria on Tumor Response.

[0292] In various embodiments, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject a GTP hydrolysis-promoting compound RAS(ON) of the present disclosure, or a pharmaceutically acceptable salt thereof, and optionally an additional therapeutic agent (e.g., a RAS(OFF) inhibitor, RTK inhibitor, Petition 870250108725, dated 11 / 27 / 2025, pp. 297 / 351 117 / 165 SHP2 inhibitor or SOS1 inhibitor) as described herein, in which the subject cannot tolerate standard therapy, first-line therapy, second-line therapy, or third-line therapy. In several embodiments, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject a GTP hydrolysis-promoting compound RAS(ON) of the present disclosure, or a pharmaceutically acceptable salt thereof, and optionally an additional therapeutic agent (e.g., a RAS(OFF) inhibitor, RTK inhibitor, SHP2 inhibitor, or SOS1 inhibitor) as described herein, in which the subject has experienced tumor recurrence after surgical resection of the primary tumor.In several embodiments, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject a GTP hydrolysis-promoting compound RAS(ON) of the present disclosure, or a pharmaceutically acceptable salt thereof, and optionally an additional therapeutic agent (e.g., a RAS(OFF) inhibitor, RTK inhibitor, SHP2 inhibitor, or SOS1 inhibitor) as described herein, wherein the subject has a tumor that cannot be surgically removed. In several embodiments, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject a GTP hydrolysis-promoting compound RAS(ON) of the present disclosure, or a pharmaceutically acceptable salt thereof, and optionally an additional therapeutic agent (e.g., a RAS(OFF) inhibitor, RTK inhibitor, SHP2 inhibitor, or SOS1 inhibitor) as described herein, wherein the subject has no other treatment options available.

[0293] Several therapies used in cancer treatment (e.g., chemotherapies) are cytotoxic and are associated with significant side effects and toxicities, which are linked to poor outcomes and poor treatment response. Before administering such treatments, physicians rely on various assessment tools to help determine the risk of a Petition 870250108725, dated 11 / 27 / 2025, pp. 298 / 351 118 / 165 individuals with cancer experience toxicities and adverse events related to treatment. Based on the results of these assessments, a subject with cancer is considered intolerant to therapy if it is determined that they have an increased risk of experiencing toxicities and adverse events related to therapy, resulting in poor outcomes. Examples of assessment tools commonly used in determining therapeutic intolerance include Karnofsky Performance Status (KPS), Eastern Cooperative Oncology Group Performance Status (ECOG PS), Timed Get Up and Go (TUG), Short Physical Performance Battery (SPPB), Comprehensive Geriatric Assessment (CGA), Cancer Aging Research Group (CARG) Score, and Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH).

[0294] In some modalities, the progression of the subject's cancer is reduced or prevented. The progression of a cancer disease (for example, a cancer described here) can be assessed by one or more of several established methods. A specialist in the field may monitor a subject through direct observation to assess how the symptoms exhibited by the subject have changed (e.g., a decrease or absence of symptoms) in response to a treatment (e.g., a treatment method disclosed here). A subject may also be examined by magnetic resonance imaging, computed tomography, or PET scan to determine if a tumor has metastasized or if the size of a tumor has changed (e.g., decreased in response to a treatment (e.g., a treatment method described here)).Optionally, cells can be extracted from the subject via a biopsy or procedure, or tumor DNA can be isolated from a subject's blood, and a quantitative biochemical analysis can be conducted to assess the relative cancer burden and determine the presence or emergence of specific mutations possibly involved in resistance. Based on the results of these analyses, a specialist in the field can prescribe dosages. Petition 870250108725, dated 11 / 27 / 2025, pp. 299 / 351 119 / 165 higher / lower or more / less frequent doses of a treatment in subsequent rounds of treatment.

[0295] In several embodiments, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject a RAS(ON)GTP hydrolysis-promoting compound and, optionally, an additional therapeutic agent (e.g., a RAS(OFF) inhibitor, RTK inhibitor, SHP2 inhibitor, or SOS1 inhibitor). In several embodiments, the administration reduces tumor size or inhibits tumor growth. In several embodiments, the administration induces tumor cell death, apoptosis, or necrosis.

[0296] The methods described herein are considered to reduce tumor size or tumor burden in the subject or to reduce metastasis in the subject. In several modalities, the methods reduce tumor size by 10%, 20%, 30% or more. In several modalities, 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 about 100%, or including all values ​​and ranges that are between these values.

[0297] In one aspect, the present disclosure provides methods for treating a RAS protein-related disorder in a subject where the pathology of the RAS-related disorder is mediated, in part, through increased signaling in the RAS / MAPK pathway. In several embodiments, the method generally comprises administering to the subject a therapeutically effective amount of a RAS(ON) GTP hydrolysis-promoting compound. In some embodiments, the RAS protein-related disorder is a RASopathy. A RASopathy is a group of genetic disorders caused by mutations in genes involved in the RAS / MAPK signaling pathway. RASopathies are characterized by a range of clinical features and Petition 870250108725, dated 11 / 27 / 2025, pp. 300 / 351 Levels 120 / 165 can affect various organ systems, including the cardiovascular, musculoskeletal, neurological, and dermatological systems.

[0298] In one aspect, the present disclosure is directed to methods of treating a disease or disorder that is characterized by aberrant RAS activity (e.g., cancer or a RASopathy). In some embodiments, the disease or disorder is cancer (e.g., a cancer with one or more RAS mutations that cause aberrant RAS activity). Non-limiting examples of non-cancerous RAS-related diseases or disorders are shown in Table 3. In each embodiment, the method generally comprises administering to the subject a therapeutically effective amount of a RAS(ON) GTP hydrolysis-promoting compound. In some embodiments, the methods comprise administering the RAS(ON) GTP hydrolysis-promoting compound in combination with one or more therapeutic agents. Suitable RAS(ON) GTP hydrolysis-promoting compounds and additional therapeutic agents are described herein. Table 3: Non-carcinogenic indications related to exemplary RAS Disease or disorder References Immune disease Autoimmune disease Journal of Clinical Immunology vol.35, pp.454-458 (2015) Rheumatoid arthritis The Open Rheumatoid Journal vol.6, pp.259-272 (2012) RAS-related autoimmune lymphoproliferative disorders PNAS vol.104, pp.8953-8958 (2007) Blood vol.117, pp.2887-2890 (2011) Infection Influenza Cancer Research vol.61, pp.8188-8193 (2001) PloS ONE vol.6, el6324 (2011) Seikagaku: The Journal of the Japanese Biochemical Society vol.87, Issue 1 Infection EBV Oncogene vol.23, pp.8619-8628 (2004) Infection HIV Journal of Biological Chemstry vol.275, pp.16513-16517 (2000) Neurological disease Alzheimer's disease Biochimica et Biophysica Acta vol.1802, pp.396-405 (2010) Neurobiology of Disease vol.43, pp.3845 (2011) Petition 870250108725, dated 11 / 27 / 2025, pp. 301 / 351 121 / 165 Disease or disorder References Parkinson's disease Biochimica et Biophysica Acta vol.1802, pp.396-405 (2010) ALS Biochimica et Biophysica Acta vol.1802, pp.396-405 (2010) RAS / MAPK syndrome Noonan syndrome Human Molecular Genetics vol.15, pp.R220-R226 (2006) Costello syndrome Genetics in Medicine vol.14, pp.285-292 (2012) CFC syndrome Human Mutation vol.29, pp.992-1006 (2008) Other diseases or disorders Cirrhosis / Chronic hepatitis Gastroenterologia Japonica vol.24, pp.270-276 (1989) Memory impairment Nature Communications vol.7, 12926 (2016)

[0299] In some modalities, the methods include treatment of a selected RASopathy from among Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, neurofibromatosis type 1, and Legius syndrome. Although each RASopathy has unique characteristics, they all share certain similarities, such as facial dysmorphisms, cardiac abnormalities, developmental delays, and an increased risk of certain types of cancer.

[0300] RASopathies are typically diagnosed through a combination of clinical evaluation, genetic testing, and imaging studies. Treatment and management of RASopathies depend on the specific type and severity of the disorder, but may include medication, surgery, and supportive therapies such as physical therapy and occupational therapy. a) Combination Therapies

[0301] Disclosure methods may include a disclosure RAS(ON)GTP hydrolysis-promoting compound in combination with an additional therapeutic agent (e.g., non-drug treatments or therapeutic agents). Dosages of one or more of the additional therapies (e.g., non-drug treatments or therapeutic agents) may be reduced relative to standard dosages when administered alone. Petition 870250108725, dated 11 / 27 / 2025, pp. 302 / 351 122 / 165 For example, doses can be determined empirically from drug combinations and permutations or can be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).

[0302] A compound of the present disclosure may be administered before, after, or concurrently with one or more of these additional therapies. When combined, dosages of a compound of the disclosure and dosages of one or more additional therapies (e.g., non-drug treatment or therapeutic agent) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). A compound of the present disclosure and an additional therapy, such as an anticancer agent, may be administered together, such as in a single pharmaceutical composition, or separately, and when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be near or far in time.

[0303] In some embodiments, additional therapy is the administration of side-effect limiting agents (e.g., agents intended to decrease the occurrence or severity of treatment side effects). For example, in some embodiments, the compounds of this disclosure may also be used in combination with a therapeutic agent that treats nausea. Examples of agents that may be used in the treatment of nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or pharmaceutically acceptable salts thereof.

[0304] In some modalities, one or more additional therapies include a non-drug treatment (e.g., surgery or radiation therapy). In some modalities, one or more additional therapies include a therapeutic agent (e.g., a compound or biologic that is an antiangiogenic agent, signal transduction inhibitor, agent Petition 870250108725, dated 11 / 27 / 2025, pp. 303 / 351 123 / 165 antiproliferative, glycolysis inhibitor, or autophagy inhibitor). In some embodiments, the one or more additional therapies include a non-drug treatment (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biologic that is an antiangiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). In another embodiment, the one or more additional therapies include two therapeutic agents. In yet another embodiment, the one or more additional therapies include three therapeutic agents. In some embodiments, the one or more additional therapies include four or more therapeutic agents.

[0305] In this Combined Therapy section, all references are incorporated by reference to the agents described, whether explicitly stated as such or not. i) Non-Drug Therapies

[0306] Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and adoptive T-cell transfer (ACT) therapy.

[0307] In some modalities, the disclosure compounds can be used as adjuvant therapy after surgery. In some modalities, the disclosure compounds can be used as neoadjuvant therapy before surgery.

[0308] Radiation therapy can be used to inhibit abnormal cell growth or to treat a hyperproliferative disorder, such as cancer, in a subject (e.g., mammal (e.g., human)). Techniques for administering radiotherapy are known in the art. Radiotherapy can be administered by one of several methods or a combination of methods, including, without limitation, external beam therapy, internal radiotherapy, implant radiation, stereotactic radiosurgery, systemic radiotherapy, Petition 870250108725, dated 11 / 27 / 2025, pp. 304 / 351 124 / 165 radiotherapy and permanent or temporary interstitial brachytherapy. The term brachytherapy, as used in this document, refers to radiotherapy delivered by a 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, without limitation, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32 and radioactive isotopes of Lu). Radiation sources suitable for use as a cell conditioner in this disclosure include both solids and liquids. As a non-limiting example, the radiation source may be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic rays.Radioactive material can also be a fluid made from any solution of radionuclide(s), for example, a solution of I-125 or I-131, or a radioactive fluid can be produced using a paste of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Furthermore, the radionuclide(s) can be incorporated in the form of a gel or radioactive microspheres.

[0309] In some embodiments, the compounds of this disclosure can make abnormal cells more sensitive to radiation treatment for the purpose of killing or inhibiting the growth of such cells. Therefore, this disclosure further refers to a method for sensitizing abnormal cells in a mammal to radiation treatment comprising administering to the mammal an amount of a compound of this disclosure, the amount of which is effective in sensitizing abnormal cells to radiation treatment. The amount of the compound in this method can be determined according to the means for confirming effective amounts of such compounds described herein. In some Petition 870250108725, dated 11 / 27 / 2025, pp. 305 / 351 125 / 165 modalities, the compounds of this disclosure may be used as adjuvant therapy after radiation therapy or as neoadjuvant therapy before radiation therapy.

[0310] In some embodiments, the non-drug treatment is an adoptive T-cell transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. The T cell can be modified to express a chimeric antigen receptor (CAR). CAR-modified T cells (CART) 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 the CAR into a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from various sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present disclosure, any number of T cell lines available in the art can be used.In some embodiments, the T cell is an autologous T cell. Whether before or after genetic modification of T cells to express a desirable protein (e.g., a CAR), T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964;. 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041. ii) Therapeutic agents

[0311] A therapeutic agent can be a compound used in the treatment of cancer or symptoms associated with it.

[0312] For example, a therapeutic agent may be a steroid. Therefore, in some modalities, one or more additional therapies are used. Petition 870250108725, dated 11 / 27 / 2025, pp. 306 / 351 126 / 165 include a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, ancinonide, beclometasone, betamethasone, budesonide, chlorprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, butyl fluocortin, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halomethasone, hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednilidene,rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide and salts or derivatives thereof.

[0313] Other examples of therapeutic agents that may be used in combination therapy with a compound of the present disclosure include compounds described in the following patents: U.S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141. 6,235,764 and 8,623,885, and International Patent Applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089, and WO00 / 02871.

[0314] A therapeutic agent may be a biologic (e.g., cytokine (e.g., interferon or an interleukin, such as IL-2)) used in the treatment of cancer or symptoms associated with it. In some modalities, the biologic is an immunoglobulin-based biologic, for example, Petition 870250108725, dated 11 / 27 / 2025, pp. 307 / 351 127 / 165 a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to elicit an anticancer response or antagonizes an antigen important for cancer. Antibody-drug conjugates are also included.

[0315] A 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, for example, an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with the 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 a fusion protein).In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L1. 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, CHK 1, CHK2, A2aR, and B-7 family ligands. Petition 870250108725, dated 11 / 27 / 2025, pp. 308 / 351 128 / 165 or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody, such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9 and KW-6002.

[0316] A therapeutic agent may be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A or OMP-313M32 (etigilimab).

[0317] A therapeutic agent may be an agent that treats cancer or symptoms associated with it (for example, a cytotoxic agent, small non-peptidic molecules, or other compound useful in the treatment of cancer or symptoms associated with it, collectively, an anticancer agent). Anticancer agents may be, for example, chemotherapeutic agents or targeted therapy agents.

[0318] Anticancer agents include mitotic inhibitors, intercalating 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, epipodopilotoxines, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted urea, methylhydrazine derivatives, adrenocortical suppressant, adrenocorticosteroids, progestogens, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Petition 870250108725, dated 11 / 27 / 2025, pp. 309 / 351 129 / 165 Other anticancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some modalities, one or more additional therapies include two or more anticancer agents. The two or more anticancer agents may be used in a cocktail to be administered in combination or administered separately. Appropriate dosage regimens for combination anticancer agents are known in the art and 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).

[0319] Other non-limiting examples of anticancer agents include Gleevec® (Imatinib Mesyldate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamylamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bulatacin and bulatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; calistatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin and bizelesin); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues KW2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictin A; spongistatin;Nitrogenous disodium, such as chlorambucil, chloranaphazene, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicine, fenesterine, prednimustine, trofosfamide, uracil disodium; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enedine antibiotics (e.g., calicheamicin, such as calicheamicin gamma I and calicheamicin omega II (see, for example, Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); Petition 870250108725, dated 11 / 27 / 2025, pp. 310 / 351 130 / 165 dynecin, including dynecin A; bisphosphonates, such as clodronate; esperamycin; as well as neocarzinostatin chromophore and related chromoprotein enedin antibiotic chromophores), aclacinomissins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophylline, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxidoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porphyromycin, puromycin, chelamycin, rhodorubicin, Streptonigrin, streptozocin, tubercidine, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate;Purine analogs such as fludarabine, 6-mercaptopurine, tiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cotarabine, dideoxyuridine, doxyfluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglathine; aldofosfamide glycoside; aminolevulinic acid; enyluracil; amsacrine; bestrabucil; bisanthrene; edatraxate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; epothilone; etoglucoside; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerin; pentostatin; fenamete; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydraniza; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxine;Sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''trichlorotriethylamine; trichothecenes such as T-2 toxin, verracurin A, roridine A and; Petition 870250108725, dated 11 / 27 / 2025, pages 311 / 351 131 / 165 anguidine; urethane; vindesine; dacarbazine; manomustine; mitobronitol; mitolactol; pipobromane; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, for example, Taxol® (paclitaxel), Abraxane® (cremophor-free, engineered nanoparticle formulation with paclitaxel albumin), and Taxotere® (docetaxel); chlorambucil; tamoxifen (Nolvadex™); raloxifene; 4(5)-imidaze aromatase inhibitors; 4-hydroxytamoxifen; trioxifene; ceoxifene; LY 117018; onapristone; toremifene (Fareston®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® (vinorelbine); novantron; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esperamycins (e.g., Xeloda®); and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0320] Additional, but not limiting, examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicin, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfaradine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastics (e.g., cell cycle nonspecific antineoplastic agents and other antineoplastics described herein), antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostalicin, briostatin, butionine sulfoximine, CBV (chemotherapy), caliculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesin, fosfestrol, regimen of Petition 870250108725, dated 11 / 27 / 2025, pp. 312 / 351 132 / 165 chemotherapy ICE, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 and zosuquidar.

[0321] Other non-limiting examples of anticancer agents include natural products such as 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, bleomycins, plicamycin (mitramycin), mitomycin, enzymes (e.g., L-asparaginase which systemically metabolizes L-asparagine and deprives cells that lack the ability to synthesize their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogues, melphalan, and chlorambucil), ethyleneimines, and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., a CDK4 / 6 inhibitor such as abemaciclib, ribociclib, palbociclib;seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638 and; SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogues, and streptozocin), trazenosdacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites, such as folic acid analogues, pyrimidine analogues (e.g., fluorouracil, floxuridine and cytarabine), purine analogues and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine), Petition 870250108725, dated 11 / 27 / 2025, pp. 313 / 351 133 / 165 aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole) and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binding agents (e.g., Zalypsis®), PI3K inhibitors, such as PI3K delta inhibitor (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitor (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; multikinase inhibitor (e.g., TG02 and sorafenib), hormones (e.g., estrogen), and hormone agonists, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g.,goserelin, leuprolide and triptorelin), BAFF neutralizing antibody (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.

[0322] In some embodiments, an anticancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, Petition 870250108725, dated 11 / 27 / 2025, pp. 314 / 351 134 / 165 gemcitabine, Navelbine®, sorafenib, or any analogue or variant derived from the foregoing.

[0323] In some embodiments, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; 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 document WO05016894.

[0324] In some embodiments, an anticancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., an SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY1971, ERAS-601, SH3809, PF-07284892 or BBP-398 or any other SHP2 inhibitor known in the art), an SOS1 inhibitor (e.g., RMC-5845, BI-1701963, BI-3406, SDR5 or BAY-293 or any other SHP2 inhibitor known in the art), a RAS inhibitor (e.g., BI-2852 or any RAS inhibitor known in the art), a RAS inhibitor A degrading agent, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., mTORC1 inhibitor or mTORC2 inhibitor). In some embodiments, the anticancer agent is JAB-3312.

[0325] In some embodiments, a therapeutic agent that may be combined with a compound of the present disclosure is a MAP kinase (MAPK) pathway inhibitor (or “MAPK inhibitor”). MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancers (Basel) September 2015; 7(3): 1758-1784. For example, the MAPK inhibitor may be selected from one or more of trametinib, binimetinib, Petition 870250108725, dated 11 / 27 / 2025, pp. 315 / 351 135 / 165 selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA 119 / BAY 86-9766); GDC0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, described in PLoS One. November 25, 2014;9(11)); and GSK1120212 (or JTP74057, described in Clin Cancer Res. March 1, 2011;17(5):989-1000). The MAPK inhibitor may be PLX8394, LXH254, GDC-5573, or LY3009120.

[0326] In some embodiments, an anticancer agent is a disruptor or inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathways. The PI3K / AKT inhibitor may include, but is not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) September 2015; 7(3): 1758-1784. For example, the PI3K / AKT inhibitor may be selected from one or more of NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0327] In some embodiments, an anticancer agent is a PD-1 or PD-L1 antagonist.

[0328] In some modalities, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immune therapies, such as an immune checkpoint inhibitor.

[0329] MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, a 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. Petition 870250108725, dated 11 / 27 / 2025, p. 316 / 351 136 / 165 Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.

[0330] PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs described in WO06 / 044453; 4[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO06 / 122806); (S)-1-(4-((2-(2aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740); LY294002 (2-(4morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (available from Axon Medchem); PI hydrochloride 103 (3-[4-(4-morpholinylpyrido-[3',2' :4,5]furo[3,2d]pyrimidin-2-yl] phenol hydrochloride (available from Axon Medchem); PIK 75 (2-methyl-5-nitro-2[(6-bromo[1,2[1,2[1,2] hydrochloride); -a]pyridin-3-yl)methylene]-1 -methylhydrazidebenzenosulfonic acid, monochloride) (available from Axon Medchem) PIK 90 (N(7,8-dimethoxy-2,3-di-hydro-imidazo[l, 2-c]quinazolin-5-yl)-namide (available from Axon Medchem); Medchem ); -(phenylamino)ethyl]- 4H-pyrido-[1,2-a]pyrinidin-4-one (available from Axon Medchem XL-765 and XL-147) Other PI3K inhibitors include demethoxyviridine, perifosine, CAL101, PX-862, BEZ1316; INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI- 103, GNE-477, CUDC-907 and AEZS-136.

[0331] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem. J. 2005, 385 (Pt. 2): 399-408); Akt1-1,2 (inhibits Aktl and 2) (Barnett et al., Biochem. J. 2005, 385 (Pt. 2): 399-408); API59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91: 1808-12); compounds Petition 870250108725, dated 11 / 27 / 2025, pp. 317 / 351 137 / 165 1-H-imidazo[4,5-c]pyridinyl (e.g., WO 05 / 011700); indole-3-carbinol and its derivatives (e.g., US Patent No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Suppl):3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15):524-252); lipid analogs of phosphatidylinositol ether (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13: 787-97); and tricyribrine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9).

[0332] mTOR inhibitors include, but are not limited to, competitive mTORC1 / mTORC2 ATP inhibitors, for example, PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94 / 09010); sapanasertib, ridaforolimus (also known as deforolimus or AP23573); rapalogs, for example, as disclosed in WO98 / 02441 and WO01 / 14387, for example, AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazol)-rapamycin (also called ABT578); 32-desoxorapamycin; 16-pentiniloxy-32(S)-dihydrorapanicin; derivatives disclosed in WO05 / 005434; derivatives disclosed in 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 in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, for example, WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552.

[0333] BRAF inhibitors that can be used in combination with disclosure compounds include, for example, vemurafenib, Petition 870250108725, dated 11 / 27 / 2025, pp. 318 / 351 138 / 165 dabrafenib and encorafenib. A BRAF mutation may comprise a BRAF Class 3 mutation. In some embodiments, the BRAF Class 3 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.

[0334] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia protein-1 (MCL-1) is one of the major anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 has been closely associated with tumor progression as well as resistance, not only to traditional chemotherapies but also to targeted therapies, including BCL-2 inhibitors such as ABT-263.

[0335] In some embodiments, the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, a HER2 inhibitor, an SHP2 inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, an SOS1 inhibitor, and a PD-L1 inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, an SHP2 inhibitor, and a PD-L1 inhibitor. 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, a Ras inhibitor from this disclosure is used in combination with a MEK inhibitor and an SOS1 inhibitor. In some embodiments, a Ras inhibitor from this disclosure is used in combination with a PD-L1 inhibitor and an SOS1 inhibitor. In some embodiments, a Ras inhibitor from this disclosure is used in combination with a PD-L1 inhibitor and an SHP2 inhibitor.In some embodiments, a Ras inhibitor from this disclosure is used in combination with a MEK inhibitor and an SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer and the treatment comprises... Petition 870250108725, dated 11 / 27 / 2025, pp. 319 / 351 139 / 165 administration of a Ras inhibitor from this disclosure in combination with a second or third therapeutic agent.

[0336] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®) and oprozomib.

[0337] Immune therapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically modified T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1, anti-PD-L1, anti-CTLA4, anti-LAG1, and anti-OX40 agents.

[0338] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that adjust immune responses) containing an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0339] Examples of anti-PD-1 antibodies and methods for their use are described by Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168 A1), as well as described elsewhere in this document.

[0340] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as a GITR fusion protein described in U.S. Patent No. 6,111,090, U.S. Pat. No. 8,586,023, WO2010 / 003118 and WO2011 / 090754; or an anti-GITR antibody described, for example, in US Patent No. 7,025,962, EP 1947183, US Patent No. 7,812,135, US Patent No. 8,388,967, US Patent No. 8,591,886, US Patent No. 7,618,632, EP 1866339 and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451 and WO2011 / 051726.

[0341] Another example of a therapeutic agent that can be Petition 870250108725, dated 11 / 27 / 2025, pp. 320 / 351 140 / 165 used in combination with the disclosure compounds is an antiangiogenic agent. Antiangiogenic agents include, but are not limited to, synthetically prepared chemical compositions in vitro, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. An antiangiogenic agent may be an agonist, antagonist, allosteric modulator, toxin, or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition) and thus promote cell death or halt cell growth. In some modalities, one or more additional therapies include an antiangiogenic agent.

[0342] Antiangiogenic agents may be MMP2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of antiangiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085 and US Patent Nos. 5,863,949 and 5,961,510. Preferred inhibitors of MMP-2 and MMP-9 are those that have little or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG3340, RO 32-3555, and RS 13-0830. Petition 870250108725, dated 11 / 27 / 2025, pp. 321 / 351 141 / 165

[0343] Other examples of antiangiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen-binding regions that specifically bind to VEGF (e.g., bevacizumab), or soluble VEGF receptors or a ligand-binding region thereof), such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind to them), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 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 antigens). Other antiangiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., antibodies specifically binding to antigen-binding regions or soluble antagonists of the TWEAK receptor; see US6,727,225), ADAM distintegrin domain to antagonize integrin binding to its ligands (US 2002 / 0042368), specifically binding to the anti-eph receptor or anti-ephrin antibodies or antigen-binding regions (US Patents Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and members of the patent family thereof) and antagonists anti-PDGF-BB (e.g., specific binding antibodies or antigen-binding regions),as well as antibodies or antigen-binding regions that bind specifically to PDGFBB ligands and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that bind specifically to them). Agents, Petition 870250108725, dated 11 / 27 / 2025, pp. 322 / 351 Additional 142 / 165 antiangiogenic drugs include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium (Gilead Sciences, USA); Alfastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastate (Arriva, USA, US 5892112); emaxanib (Pfizer, USA, US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); alfa-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands), DACantiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT technology (Ariad, USA); YIGSRStealth (Johnson & Johnson, USA); fibrinogen-E fragment (BioActa, UK); angiogenic 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); ER68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); platelet factor 4 (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenic inhibitors (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); MAb, alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, USA);Enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); antiangiogenic derived from rBPI 21 and BPI (XOMA, USA); PI 88 (Progen, Australia); cilengitide (Merck KGaA, Germany; Munich Technical University, Germany; Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston; Petition 870250108725, dated 11 / 27 / 2025, pp. 323 / 351 143 / 165 Children's Hospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitors, (EntreMed, USA); pegaptanib (PINN), (Gilead Sciences, USA); xanthorrhizole, (Yonsei University, South Korea); VEGF-2 gene-based vaccine, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California at San Diego, USA); PX 478, (ProlX, USA); METASTATIN, (EntreMed, USA); troponin I, (Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE, USA); o-guanidines, (Dimensional Pharmaceuticals, USA); motuporamine C, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); angiogenic vaccine, (EntreMed, USA);Plasminogen urokinase activator inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA); HIF-1alpha inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA); KR 31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); intraocular drug delivery system, 2-methoxyestradiol; Anginex (Maastricht University, Netherlands and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor alpha inhibitors; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, alpha5 beta (Protein Design, USA);KDR kinase inhibitor (Celltech Group, UK, and Johnson & Johnson, USA); Petition 870250108725, dated 11 / 27 / 2025, pp. 324 / 351 144 / 165 GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); irsogladine (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine (Genaera, USA); RPI 4610 (Sirna, USA); Heparanase inhibitors (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE-cadherin-2 antagonists (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA);Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligands (Regeneron, USA); and thrombospondin inhibitor 1 (Allegheny Health, Education and Research Foundation, USA).

[0344] Other examples of therapeutic agents that can be used in combination with compounds of the invention include agents (e.g., antibodies, antigen-binding regions or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as hepatocyte growth factor (HGF, also known as Dispersing Factor) antagonists, and antibodies or antigen-binding regions that specifically bind to their receptor, c-Met.

[0345] Another example of a therapeutic agent that can be used in combination with disclosure compounds is an autophagy agent. Autophagy inhibitors include, but are not limited to, Petition 870250108725, dated 11 / 27 / 2025, pp. 325 / 351 145 / 165 chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, algal toxins that suppress autophagy and inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNAs that inhibit the expression of proteins including, but not limited to, ATG5 (which are implicated in autophagy) may also be used. In some modalities, one or more additional therapies include an autophagy inhibitor.

[0346] Another example of a therapeutic agent that can be used in combination with disclosure compounds is an antineoplastic agent. In some modalities, one or more additional therapies include an antineoplastic agent. Non-limiting examples of antineoplastic agents include acemannan, aclarubicin, aldesleucin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestortim, arglabine, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmolleucin, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, DA 3030 (Dong-A), daclizumab, denileucin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxyfluridine, dox or rubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, issita,epirubicin, epoetin beta, etoposide phosphate, exemenenene, exeminide, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gentuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibadronic acid, idarubicin, (imiquimod, interferon alpha, interferon alpha, natural, interferon alpha-2, interferon, Petition 870250108725, dated 11 / 27 / 2025, pp. 326 / 351 146 / 165 alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha-N3, interferon alpha-1, interferon alpha, natural, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentin sulfate, letrozole, leukocyte interferon alpha, leuprorelin, levamisole + fluorouracil, liarozole, loboplatin, lonidamine, lovastatin, masoprocol, melaraprol, metoclopramide, mifepristone, miltefosine, mirmostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartagrasm utamide, noscapine, new erythropoiesis-stimulating protein, NSC 631570 octreotide, oprel vekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin,rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, sodium porfimer, raloxifene, raltitrexed, Rasburiembodiment, rhenium etidronate 186, RII retinamide, rituximab, romurtide, samarium (153 Sm), Lexidronam, Sargogram, sizofiran, sobuzoxaxane, Sonermin, stonium chloride-89, suramin, tasonermin, tazarotene, tegafur, temoporfin, temosolomide, teniposide, tetrachloridecaoxide, thalidomide, timalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizine, zinostatin or zoledronic acid estimalamer; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan),EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor dihydrochloride, Petition 870250108725, dated 11 / 27 / 2025, pp. 327 / 351 Histamine 147 / 165, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifen, LDI 200 (Milkhaus), leridistim, lintuzumab, MAb CA 125 (Biomira), cancer MAb (Japan Pharmaceutical Development), MAb HER-2 and Fc (Medarex), MAb 105AD7 idiotypic (CRC Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techni clone), polymorphic epithelial mucin 90 Yttrium MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), Nelarabine, Nolatrexed, Protein P 30, Pegvisomant, pemetrexed, porphyromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparphosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, taliblastin, thrombopoietin, ethyl ethiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), oncolytic melanoma vaccine (New York Medical College),Viral melanoma cell lysate vaccine (Royal Newcastle Hospital) or Valspodar.

[0347] Additional examples of therapeutic agents that may be used in combination with disclosure compounds include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; atacicept; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); adotrastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (ADCETRIS®); canakinumab (Ilaris®); Certolizumab pegal (Cimzia®); daclizumab (Zenapax®); daratumumab (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®); gentuzumab Petition 870250108725, dated 11 / 27 / 2025, p. 328 / 351 148 / 165 ozogamicin (Mylotarg®); golima (Symphony®); ibritumomabe thioxetane (Zevalin®); inflicts (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumuma (Arzerra®); omalizumab (Xolair®); palyvizumab (Synagis®); pertuzuma (Pearl®); pertuzuma (Pearl®); ranibizumab (Lucentis®); raxibacumabe (Abthrax®); tocilizumab (Actemra®); customers; tumorigenesis-131; toximab and toxoplasmomab-131 (Bexar®)); ustequinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0348] The compounds described in this document may be used in combination with the agents disclosed in this document or other suitable agents, depending on the condition being treated. Therefore, in some embodiments, one or more compounds of the disclosure will be co-administered with other therapies, as described in this document. When used in combination therapy, the compounds described herein may be administered with the second agent simultaneously or separately. This combination administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described herein may be formulated together in the same dosage form and administered simultaneously.Alternatively, a compound from this disclosure and any of the therapies described in this document may be administered simultaneously, where both agents are present in separate formulations. Alternatively, a compound from this disclosure may be administered followed by any of the therapies described in this document, or vice versa. In some modalities of the separate administration protocol, a compound from this disclosure and any of the therapies described in this document are administered within a few minutes of each other. Petition 870250108725, dated 11 / 27 / 2025, pp. 329 / 351 149 / 165 interval, or a few hours interval, or a few days interval.

[0349] In some embodiments of any of the methods described in this document, the first therapy (e.g., a disclosure compound) and one or more additional therapies are administered simultaneously or sequentially, in any order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1 to 7, 1 to 14, 1 to 21 or 1 to 30 days before or after one or more additional therapies.

[0350] The disclosure also features kits including (a) a pharmaceutical composition including an agent (e.g., a compound from the disclosure) described herein, and (b) a package insert with instructions for performing any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent (e.g., a compound from the disclosure) described in this document, (b) one or more additional therapies (e.g., non-drug treatment or therapeutic agent) and (c) a package insert with instructions for performing any of the methods described in this document.

[0351] As one aspect of this disclosure contemplates the treatment of the disease or associated symptoms with a combination of pharmaceutically active compounds that can be administered separately, the disclosure further refers to the combination of separate pharmaceutical compositions in kit form. The kit may comprise two separate pharmaceutical compositions: a compound from this disclosure and one or more additional therapies. The kit may comprise a container for holding the separate compositions, such as a divided bottle or a divided foil pack. Additional examples of containers Petition 870250108725, dated 11 / 27 / 2025, pp. 330 / 351 150 / 165 kits include syringes, boxes, and bags. In some embodiments, the kit may include instructions for the use of 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), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the healthcare professional's prescription. Modalities

[0352] Modality 1: A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a RAS(ON) hydrolysis-promoting compound, wherein the cancer does not comprise a RAS mutation at position 61.

[0353] Modality 2: A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a GTP hydrolysis promoter RAS(ON) compound and a RAS(OFF) inhibitor, wherein the cancer does not comprise a RAS mutation at position 61.

[0354] Modality 3: A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a GTP hydrolysis-promoting compound RAS(ON) and an RTK inhibitor, wherein the cancer does not comprise a RAS mutation at position 61.

[0355] Modality 4: A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a GTP hydrolysis-promoting compound RAS(ON) and an SHP inhibitor (e.g., an SHP2 inhibitor), wherein the cancer does not comprise a RAS mutation at position 61. Petition 870250108725, dated 11 / 27 / 2025, pages 331 / 351 151 / 165

[0356] Modality 5: A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a GTP hydrolysis-promoting compound RAS(ON) and an SOS1 inhibitor, wherein the cancer does not comprise a RAS mutation at position 61.

[0357] Modality 6: The method of any of the Modalities 1 to 5, in which the cancer comprises a RAS mutation.

[0358] Mode 7: The method of Mode 6, in which the RAS mutation is an RAS amplification or the RAS mutation is at position 12 or 13.

[0359] Modality 8: The method of Modalities 1 to 7, in which the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer, or uterine cancer.

[0360] Embodiment 9: The method of any of Embodiments 1 to 8, in which the binding of the GTP hydrolysis-promoting compound RAS(ON) to RAS(ON) alters the position of glutamine 61 of RAS(ON), relative to the position in the absence of the GTP hydrolysis-promoting compound RAS(ON), towards the gamma phosphate of GTP bound to the RAS(ON) protein, thereby increasing the rate of GTP hydrolysis relative to the rate of RAS(ON) hydrolysis in the absence of the GTP hydrolysis-promoting compound RAS(ON).

[0361] Embodiment 10: The method of any of the Embodiments 1 to 9, wherein the GTP hydrolysis promoting compound RAS(ON) is a compound from Table 1 or a pharmaceutically acceptable salt thereof.

[0362] Modality 11: The method of any of the Modes 2 or 6 to 10, where the RAS(OFF) inhibitor is a KRAS(OFF) inhibitor.

[0363] Modality 12: The method of Modality 11, where the KRAS(OFF) inhibitor is a KRASG12C(OFF) inhibitor. Petition 870250108725, dated 11 / 27 / 2025, pp. 332 / 351 152 / 165

[0364] Embodiment 13: The method of Embodiment 12, in which the KRASG12C(OFF) inhibitor is selected from the group consisting of AMG510 (sotorasib), MRTX849 (adagrasib), MRTX1257, GDC-6036 (divarasib), JDQ443 (opnurasib), ERAS-3490, LY3537982 (olomorasib) FMC-376, GEC255 and GFH925 (IBI351).

[0365] Modality 14: The method of Modality 11, in which the KRAS(OFF) inhibitor is a KRASG12D(OFF) inhibitor.

[0366] Modality 15: The Modality 14 method, in which the KRASG12D(OFF) inhibitor is selected from the group consisting of MRTX1133, MRTX282, JAB-22000, ERAS-4, ERAS-5024, HRS-4642, BI-2852, ASP3082, TH-Z827, TH-7835, QTX-3046, GFH375 (VS-7375), INCB161734 and KD-8.

[0367] Modality 16: The method of Modality 11, in which the KRAS(OFF) inhibitor is a KRASG12V(OFF) inhibitor.

[0368] Mode 17: The method of Mode 16, in which the KRASG12V(OFF) inhibitor is JAB-23000.

[0369] Modality 18: The method of Modality 11, in which the KRAS(OFF) inhibitor is a pan-RAS(OFF) inhibitor.

[0370] Modality 19: The method of Modality 18, in which the pan-RAS(OFF) inhibitor is JAB-23400, JAB-23425, BI-2493, BI-2865, QTX3034, QTX3544, ZG2001, BBO-a, BBO-B, or pan KRas-IN-1.

[0371] Modality 20: The method of any of the Modalities 4 or 6 to 10, wherein the SHP2 inhibitor is selected from SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, BBP-398 or any combination thereof.

[0372] Modality 21: The method of any of the Modes 5 to 10, in which the SOS1 inhibitor is selected from RMC-5845, Petition 870250108725, dated 11 / 27 / 2025, pp. 333 / 351 153 / 165 RMC-4948, RMC-0331, BI-1701963, BI-3406, SDR5, MRTX0902, BAY-293 or any combination thereof.

[0373] Modality 22: The method of any of the Modalities 1 to 21, in which the GTP hydrolysis-promoting compound RAS(ON) and the RAS(OFF) inhibitor, SHP2 inhibitor, RTK inhibitor, or SOS1 inhibitor are administered on the same day.

[0374] Modality 23: The method of any of the Modalities 1 to 21, in which the GTP hydrolysis-promoting compound RAS(ON) and the RAS(OFF) inhibitor, SHP2 inhibitor, RTK inhibitor, or SOS1 inhibitor are administered simultaneously or sequentially.

[0375] Modality 24: The method of any of the Modalities 1 to 21, in which the GTP hydrolysis-promoting compound RAS(ON) and the RAS(OFF) inhibitor, SHP2 inhibitor, RTK inhibitor, or SOS1 inhibitor are administered on different days.

[0376] Modality 25: The method of any of the Modalities 1 to 22, in which the method also includes administering additional anticancer therapy.

[0377] Modality 26: The Modality 25 method, in which the additional anticancer therapy is an EGFR inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, an immune checkpoint inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, an RTK inhibitor, or a combination thereof.

[0378] Modality 27: The method of Modality 26, in which the immune checkpoint inhibitor is a PD-L1 inhibitor or a PD-1 inhibitor.

[0379] Modality 28: A method for treating a RAS protein-related disorder in a subject in need thereof, the method Petition 870250108725, dated 11 / 27 / 2025, pp. 334 / 351 154 / 165 comprising administering to the subject a therapeutically effective amount of a GTP hydrolysis-promoting compound RAS(ON).

[0380] Modality 29: A method for treating RASopathy in a subject in need of it, the method comprising administering to the subject a therapeutically effective amount of a GTP hydrolysis-promoting compound RAS(ON).

[0381] Modality 30: The method of modality 29, in which RASopathy is cardiofaciocutaneous syndrome, Costello syndrome, Legius syndrome, neurofibromatosis type 1, Noonan syndrome or capillary malformation-arteriovenous malformation syndrome.

[0382] Modality 31: The method of any of the modalities 28 to 30, in which the method also includes the administration of an additional RASopathy therapy.

[0383] Modality 32: The method of modality 31, in which the additional therapy for RASopathy is an EGFR inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, an RTK inhibitor, or a combination thereof.

[0384] Modality 33: A method of inhibiting RAS activity in a cell, the method comprising bringing the cell into contact with an effective amount of a RAS(ON)GTP hydrolysis-promoting compound.

[0385] Embodiment 34: A method for increasing the sensitivity of a cell to a RAS(OFF) inhibitor, the method characterized in that it comprises contacting the cell with an effective amount of a GTP hydrolysis-promoting compound RAS(ON), wherein the GTP hydrolysis-promoting compound RAS(ON) synergistically increases the sensitivity of the cell to the RAS(OFF) inhibitor. Petition 870250108725, dated 11 / 27 / 2025, pages 335 / 351 155 / 165

[0386] Embodiment 35: A method for increasing the crosslinking rate of a KRASG12C(OFF) inhibitor to the cysteine ​​residue at position 12 of KRASG12C in a cell, comprising contacting the cell with an effective amount of a GTP hydrolysis-promoting compound RAS(ON).

[0387] Modality 36: A pharmaceutical composition comprising a therapeutically effective amount of a GTP hydrolysis promoter RAS(ON) and a RAS(OFF) inhibitor.

[0388] Modality 37: A kit comprising a) a RAS(ON) GTP hydrolysis promoter compound and b) a RAS(OFF) inhibitor.

[0389] Modality 38: A kit comprising a) a GTP hydrolysis promoter compound RAS(ON) and b) an RTK inhibitor.

[0390] Modality 39: A kit comprising a) a GTP hydrolysis promoter compound RAS(ON) and b) an inhibitor of SHP2.

[0391] Modality 40: A kit comprising a) a GTP hydrolysis promoter compound RAS(ON) and b) an SOS1 inhibitor.

[0392] Modality 41: The kit of any of the Modalities 37 to 40, also including an insert with instructions for administering the pharmaceutical composition(s). Other modalities

[0393] Although the disclosure has been described in relation to specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses or adaptations of the disclosure following, in general, the principles of the disclosure and including such deviations from the disclosure that come within known or customary practice within the art to which the disclosure belongs and can be applied to the essential features set forth above, and follow within the scope of the claims. Other embodiments are within the claims. Petition 870250108725, dated 11 / 27 / 2025, pp. 336 / 351 156 / 165 Examples

[0394] The disclosure is further illustrated by the following examples and summary examples, which should not be construed as limiting this disclosure in scope or spirit to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and that no limitation of the scope of this disclosure is intended hereby. It should also be understood that it is possible to have resources in various other embodiments, modifications and equivalents thereof, which may suggest the same to those skilled in the art, without departing from the spirit of the present disclosure or the scope of the appended claims. Example 1. Characterization of GTP hydrolysis-promoting compounds RAS(ON)

[0395] The hydrolysis rate of RAS GTP was evaluated in the presence of various KRAS mutations. To assess GTP hydrolysis activity, recombinant KRAS proteins (residue 1-169 of KRAS4B) were expressed in E. coli and purified using a TEV protease-cleavable His6 label and Ni2+ affinity chromatography. The His6 label was removed by treatment with TEV protease, and the KRAS protein was isolated by passing it through a second Ni2+ column followed by size exclusion chromatography. The purified KRAS proteins were loaded with GTP by incubation for 2 hours on ice with 2 mM GTP and 10 mM ethylenediaminetetraacetic acid, followed by the addition of 10 mM MgCl2 and incubation on ice for another 1 hour. Excess GTP was removed by overnight dialysis against buffer (12.5 mM HEPES, 75 mM NaCl, pH 7.5) at 4 °C. The GTP-loaded KRAS protein was flash-frozen in liquid nitrogen and then stored at -80 °C until use.

[0396] GTP-loaded KRAS proteins (1 μM) were Petition 870250108725, dated 11 / 27 / 2025, pp. 337 / 351 157 / 165 combined with 25 μM recombinant human cyclophilin A and 10 μM of compound in reaction buffer (12.5 mM HEPES, 75 mM NaCl, 1 mM MgCl2, 1 mM DTT, 1% DMSO, pH 7.5) pre-heated to 37 °C. At fixed time points, aliquots were removed and tempered by heating to 80 °C to denature the proteins and then centrifuged to sediment the protein precipitate. The supernatant was assessed for GTP levels using Promega GTPase-Glo™ according to the manufacturer's instructions. GTP levels as a function of incubation time were fitted to a single-phase exponential decay to determine the rate constant for hydrolysis activity.

[0397] All RAS mutants show increased hydrolysis in the presence of a GTP hydrolysis-promoting compound RAS(ON) (Compound E), except those with mutations of residue Q61 required for catalytic hydrolysis activity (FIG. 1). Next, the activation of RAS GTP hydrolysis was characterized using various compounds. Compound A, Compound B, and Compound C each represent a strong hydrolyzer. Compound D is a moderate hydrolyzer. Compound F represents the class that does not activate GTP hydrolysis by RAS, while the others show varying degrees of activation of RAS GTP hydrolysis (FIG. 2). The structure of Compound F is as follows: Example 2. Synergy with the combination of a GTP hydrolysis-promoting compound RAS(ON) and a nucleotide exchange inhibitor RAS.

[0398] Cell lines were seeded in complete growth medium (RPMI-1640 or DMEM with 10% fetal bovine serum and Petition 870250108725, dated 11 / 27 / 2025, pp. 338 / 351 158 / 165 1% penicillin / streptomycin) and left to adhere overnight in a humidified incubator at 37 °C and 5% CO2. For phospho(Thr202 / Tyr204; Thr185 / Tyr187)-ERK1 / 2 experiments, the compounds from the following day were added at the indicated concentrations and incubated for 4 hours. Cells were lysed, and the amount of phospho-(Thr202 / Tyr204; Thr185 / Tyr187)-ERK1 / 2 relative to total ERK1 / 2 levels was assessed using the Meso Scale Diagnostics Kit K15107D according to the manufacturer's instructions. For cell viability measurements, the compounds were added the following day at the indicated concentrations and incubated for a further 5 days. The number of viable cells in each well was assessed with Promega CellTiter-Glo® reagent according to the manufacturer's instructions. Cell viability was normalized for DMSO controls.The levels of phospho-(Thr202 / Tyr204; Thr185 / Tyr187)ERK1 / 2 or cell viability as a function of compound concentrations were plotted using GraphPad Prism. EC50 values ​​from a 4-parameter sigmoidal concentration-response value were used to calculate the potency increase as the ratio between EC50 for the RAS(ON) compound in the absence of RMC-4550 and EC50 for the RAS(ON) compound in the presence of RMC-4550.

[0399] The KRASG12D AsPC-1 mutant cell line was cultured in RPMI-1640 supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. 20,000 cells were seeded in 0.10 mL wells of a 96-well tissue culture plate. After overnight incubation, the compounds were added at the indicated concentration and incubated for a further 4 hours. The amount of phospho-(Thr202 / Tyr204; Thr185 / Tyr187)-ERK1 / 2 relative to total ERK1 / 2 levels was assessed using the Meso Scale Diagnostics Kit K15107D according to the manufacturer's instructions. The relative levels of phospho-ERK were plotted as a function of the concentration of the strong hydrolyzing compound C (FIG. 3A) or the non-strong hydrolyzing compound. Petition 870250108725, dated 11 / 27 / 2025, pp. 339 / 351 159 / 165 hydrolyzer F (FIG. 3B) in combination with DMSO or 1 μM RMC-4550. The KRASG12D AsPC-1 mutant cell line was cultured in RPMI-1640 supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. 4,000 cells were seeded in 0.10 mL wells of a 96-well tissue culture plate. Cell viability was assessed with Promega CellTiter Glo reagent, and relative cell viability was plotted as a function of the concentration of the strong hydrolyzer compound C (FIG. 3C) or the non-hydrolyzer compound F (FIG. 3D) in combination with DMSO or 1 μM RMC-4550. Example 3. Synergy with the combination of a GTP hydrolysis-promoting compound RAS(ON) and a RAS(OFF) inhibitor. HSA Synergy Model

[0400] Cell lines were seeded in complete growth medium (RPMI-1640 or DMEM with 10% fetal bovine serum and 1% penicillin / streptomycin) and allowed to adhere overnight in a humidified incubator at 37 °C and 5% CO2. The following day, the compounds were added at the indicated concentrations and incubated for a further 5 days. The number of viable cells in each well was assessed with Promega CellTiter-Glo® reagent according to the manufacturer's instructions. Cell viability was normalized to DMSO controls. Cell viability as a function of compound concentrations was plotted using GraphPad Prism and analyzed using the Combenefit software package (Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, Jodrell DI. Combenefit: an interactive platform for analysis and visualization of drug combinations. Bioinformatics. September 15, 2016;32(18):2866-8. doi: 10.1093 / bioinformatics / btw230) to evaluate synergy according to the highest single agent (HSA) synergy model (Borisy AA, Elliott PJ, Hurst NW, Lee MS, Lehar J, Price ER, Serbedzija G, Zimmermann GR, Foley MA, Stockwell BR,. Petition 870250108725, dated 11 / 27 / 2025, pages 340 / 351 160 / 165 Keith CT. Systematic discovery of multicomponent therapeutics. Proc Natl Acad Sci US A. 2003 Jun 24;100(13):7977-82. doi: 10.1073 / pnas.1337088100)).

[0401] The KRASG12D AsPC-1 mutant cell line was cultured in RPMI-1640 supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. 2500 cells were seeded in 0.15 mL wells of a 96-well tissue culture plate. After overnight incubation, the compounds were added at the indicated concentration and incubated for a further 120 hours. Cell viability was assessed with the Promega CellTiter Glo reagent, and relative cell viability was plotted as a function of the concentration of (FIG. 4A and FIG. 4G) MRTX1133 or (FIG. 4D) MRTX-282 in combination with the indicated concentration for Compound A (FIG. 4A and FIG. 4D) or Compound D (FIG. 4G), both strong hydrolyzers. The synergy between (FIG. 4B and FIG. 4H) MRTX1133 or (FIG. 4E) MRTX-282 and Compound A (FIG. 4B and 4E) or Compound D (FIG. 4H) was evaluated using the HAS synergy model. Representative points of synergistic drug combination between (FIG. 4C and FIG. 4I) MRTX1133 or (FIG.4F) MRTX-282 and Compound A (FIG. 4C and FIG. 4F) or Compound D (FIG. 4I) are highlighted.

[0402] The KRASG12D HPAC mutant cell line was cultured in RPMI-16 40 supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. 2500 cells were seeded in 0.15 mL wells of a 96-well tissue culture plate. After overnight incubation, the compounds were added at the indicated concentration and incubated for a further 120 hours. Cell viability was assessed using the Promega CellTiter Glo reagent, and relative cell viability was plotted as a function of the concentration of (FIG. 5A) MRTX1133 or (FIG. 5D) MRTX-282 in combination with the indicated concentration of Compound A. The synergy between (FIG. 5B) MRTX1133 or (FIG. 5E) MRTX-282 and Compound A was evaluated using the HAS synergy model. Representative points of the synergistic combination of Petition 870250108725, dated 11 / 27 / 2025, pages 341 / 351 161 / 165 medications between (FIG. 5C) MRTX1133 or (FIG. 5F) MRTX-282 and Compound A are highlighted.

[0403] The KRASG12D Gp2D mutant cell line was cultured in RPMI-16 40 supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. 2500 cells were seeded in 0.15 mL wells of a 96-well tissue culture plate. After overnight incubation, the compounds were added at the indicated concentration and incubated for a further 120 hours. Cell viability was assessed using the Promega CellTiter Glo reagent, and relative cell viability was plotted as a function of the concentration of (FIG. 6A) MRTX1133 or (FIG. 6D) MRTX-282 in combination with the indicated concentration of Compound A. The synergy between (FIG. 6B) MRTX1133 or (FIG. 6E) MRTX-282 and Compound A was evaluated using the HAS synergy model. Representative points of the synergistic drug combination between (FIG. 6C) MRTX1133 or (FIG. 6F) MRTX-282 and Compound A are highlighted. As a control, the same experiments were performed in HaCat (RASWT) cells using Compound D, MRTX1133, and MRTX-282.As expected, no synergy was observed (FIG. 7A to F). In the HaCaT cell line, a model of normal human skin keratinocytes, there is no increase in the antiproliferative effect when a RAS(ON) hydrolysis-promoting compound is combined with a RAS(OFF) inhibitor. On the other hand, synergistic antiproliferative effects of the combination of a RAS(ON) hydrolysis-promoting compound and a RAS(OFF) inhibitor are observed in cancer cell lines, as described above. The increased antiproliferative effect of the combined therapy in cancer-derived cells, and not in analogous normal cells, suggests an increased therapeutic effect without compromising toxicity in normal tissues.

[0404] The KRASG12C MiaPaCa2 mutant cell line was cultured in DMEM supplemented with 10% fetal bovine serum and 1% Petition 870250108725, dated 11 / 27 / 2025, pp. 342 / 351 162 / 165 penicillin / streptomycin. 2500 cells were seeded in 0.15 mL wells of a 96-well tissue culture plate. After overnight incubation, the compounds were added at the indicated concentration and incubated for a further 120 hours. Cell viability was assessed using the Promega CellTiter Glo reagent, and relative cell viability was plotted as a function of the concentration of (FIG. 8A) AMG510 or (FIG. 8D) MRTX849 in combination with the indicated concentration for Compound A. The synergy between (FIG. 8B) AMG510 or (FIG. 8E) MRTX849 and Compound A was evaluated using the HAS synergy model. Representative drug combination points between (FIG. 8C) AMG510 or (FIG. 8F) MRTX849 and Compound A are highlighted. In addition, crosslinking efficiency was examined for 1 μM of sotorasib alone, in combination with 1 μM of Compound A or in combination with 10 μM of Compound A (FIG. 9A-B).As can be observed, the crosslinking efficiency of sotorasib increases in a concentration-dependent manner in the presence of Compound A. The KRASG12C inhibitor sotorasib covalently targets the GDP-bound OFF state, resulting in a protein-drug adduct that can be observed by reduced mobility on SDS denaturing polyacrylamide gel electrophoresis. When MiaPaca-2 cells were treated with sotorasib, the amount of covalently modified KRASG12C (KRASG12C-Soto.) increased with increasing incubation time. When the same cells were treated with sotorasib in combination with 1 or 10 μM of Compound A, the amount of KRAS=-Soto. increased at each time point. The density of the KRASG12C and KRASG12C-Soto. gel bands... It can be quantified, plotted as a function of time, and fitted to a single-phase exponential model to obtain the rate constant for the KRASG12C target engagement.The combination of sotorasib and compound A results in faster covalent involvement of KRASG12Cem compared to sotorasib alone. Petition 870250108725, dated 11 / 27 / 2025, pp. 343 / 351 163 / 165

[0405] A cell assay was used to measure complexes between KRAS proteins and the RAS-binding domain (RBD) of the RAF1 kinase by nanoluciferase bioluminescence energy transfer (nanoBRET™). U2OS cells were seeded at the confluence in 3 mL of DMEM supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin (approximately 1 million cells per well). The following day, each well was transfected with 50 ng of a plasmid encoding N-terminal nanoluciferase-labeled KRAS4B and 2950 ng of a plasmid encoding a C-terminal HaloTag® RAF1 RBD (residues 51-149) using FuGENE HD reagent according to the manufacturer's instructions. The following day, each pool of transfected cells was transferred to 36 wells of a 96-well white plate in medium consisting of OptiMem without phenol red supplemented with 4% fetal bovine serum, 1% penicillin / streptomycin, and 100 nM HaloTag® NanoBRET™ 618 ligand.The following day, the substrate and compounds of the Vivazine™ nanoluciferase were added at the indicated concentration. After 4 hours of incubation, the light emitted at 460 and 618 nm was measured using a PerkinElmer Envision plate reader. The luminescence intensity at 618 nm relative to 460 nm is proportional to the number of complexes between the KRAS protein and the RAF1 RBD, a surrogate measure of active KRAS levels.

[0406] Compound E exhibited approximately similar potency for inhibition of RAS-RAF complexes in multiple KRAS variants, with modestly lower potency vs. KRAS^ (FIG. 10A). In contrast, an exemplary panKRAS(OFF) inhibitor, pan KRAS-IN-1 (CAS No.: 2791263-84-6): exhibited greater power vs RASm (Fig. 10B). A Petition 870250108725, dated 11 / 27 / 2025, pp. 344 / 351 164 / 165 potency of the various KRAS mutants correlated approximately with the predicted hydrolysis rate and was lower in KRASG12V and KRASG12R. Co-incubation with a super hydrolyzer RVMD increased the potency of the pan-KRAS(OFF) inhibitor to inhibit KRASG12V (Fig. 10C).

[0407] The mutant cell line KRASG12D AsPC-1 was cultured in RPMI-1640 supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. 2000 cells were seeded in 0.15 mL wells of a 96-well tissue culture plate. After overnight incubation, the compounds were added at the indicated concentration and incubated for a further 120 hours. Cell viability was assessed using the Promega CellTiter Glo reagent, and relative cell viability was plotted as a function of pan KRAS-IN-1 concentration in combination with the indicated concentration for Compound D (FIG. 11A) or Compound C (FIG. 11D), both strong hydrolyzers. The synergy between pan KRAS-IN-1 and Compound D (FIG. 11B) or Compound C (FIG. 11E) was evaluated using the HAS synergy model. Representative points of the synergistic drug combination between pan KRAS-IN1 and Compound D (FIG. 11C) or Compound C (FIG. 11F).

[0408] The KRASG12V Capan-2 mutant cell line was cultured in RPMI-1640 supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. 2000 cells were seeded in 0.15 mL wells of a 96-well tissue culture plate. After overnight incubation, the compounds were added at the indicated concentration and incubated for a further 120 hours. Cell viability was assessed using the Promega CellTiter Glo reagent, and relative cell viability was plotted as a function of pan KRAS-IN-1 concentration in combination with the indicated concentration for Compound D (FIG. 12A) or Compound C (FIG. 12D), both strong hydrolyzers. The synergy between pan KRAS-IN-1 and Compound D (FIG. 12B) or Compound C (FIG. 12E) was evaluated using the HAS synergy model. Points Petition 870250108725, dated 11 / 27 / 2025, pages 345 / 351 165 / 165 representative of the synergistic drug combination between pan KRAS-IN1 and Compound D (FIG. 12C) or Compound C (FIG. 12F).

[0409] The KRASG12C H358 mutant cell line was cultured in RPMI-1640 supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. 2000 cells were seeded in 0.15 mL wells of a 96-well tissue culture plate. After overnight incubation, the compounds were added at the indicated concentration and incubated for a further 120 hours. Cell viability was assessed using the Promega CellTiter Glo reagent, and relative cell viability was plotted as a function of pan KRAS-IN-1 concentration in combination with the indicated concentration for Compound D (FIG. 13A) or Compound C (FIG. 13D), both strong hydrolyzers. The synergy between pan KRAS-IN-1 and Compound D (FIG. 13B) or Compound C (FIG. 13E) was evaluated using the HAS synergy model. Representative points of the synergistic drug combination between pan KRAS-IN1 and Compound D (FIG. 13C) or Compound C (FIG. 13F).

[0410] The KRASG12R PSN1 mutant cell line was cultured in RPMI-1640 supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. 2000 cells were seeded in 0.15 mL wells of a 96-well tissue culture plate. After overnight incubation, the compounds were added at the indicated concentration and incubated for a further 120 hours. Cell viability was assessed using the Promega CellTiter Glo reagent, and relative cell viability was plotted as a function of pan KRAS-IN-1 concentration in combination with the indicated concentration for Compound D (FIG. 14A) or Compound C (FIG. 14D), both strong hydrolyzers. The synergy between pan KRAS-IN-1 and Compound D (FIG. 14B) or Compound C (FIG. 14E) was evaluated using the HAS synergy model. Representative points of the synergistic drug combination between pan KRAS-IN1 and Compound D (FIG. 14C) or Compound C (FIG. 14F). Petition 870250108725, dated 11 / 27 / 2025, pp. 346 / 351

Claims

1 / 4 Claims 1. METHOD FOR TREATING CANCER in a subject in need thereof, the method characterized by comprising administering to the subject a therapeutically effective amount of a RAS(ON) GTP hydrolysis-promoting compound and a RAS(OFF) inhibitor, wherein the cancer does not comprise a RAS mutation at position 61.

2. A METHOD FOR TREATING CANCER in a subject in need thereof, the method characterized by comprising administering to the subject a therapeutically effective amount of a RAS(ON) GTP hydrolysis-promoting compound.

3. METHOD, according to claim 2, the method characterized by further comprising administering an SHP2 inhibitor or an SOS1 inhibitor.

4. METHOD, according to claim 2, the method characterized by further comprising administering an SHP2 inhibitor, an SOS1 inhibitor or an RTK inhibitor.

5. METHOD, according to claim 3 or 4, characterized by the RAS(ON) GTP hydrolysis-promoting compound and the SHP2 inhibitor or SOS1 inhibitor being administered concomitantly or sequentially.

6. METHOD, according to claim 5, characterized by the method further comprising administering a RAS(OFF) inhibitor.

7. METHOD, according to claim 6, characterized by the RAS(OFF) inhibitor being administered concomitantly or sequentially with the GTP hydrolysis-promoting compound RAS(ON) and / or SHP2 inhibitor, SOS1 inhibitor or RTK inhibitor.

8. METHOD, according to any one of claims 1 to 7, characterized by cancer comprising a RAS mutation.

9. METHOD, according to claim 8, characterized by Petition 870250108725, dated 11 / 27 / 2025, p. 347 / 351 2 / 4 mutation RAS being in position 12 or 13.

10. METHOD, according to any one of claims 1 to 9, characterized in that the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer or uterine cancer.

11. METHOD, according to any one of claims 1 to 10, characterized in that the method further comprises administering additional anticancer therapy.

12. METHOD, according to claim 11, characterized in that the additional anticancer therapy is an EGFR inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, an immune checkpoint inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, an RTK inhibitor, or a combination thereof.

13. A METHOD FOR TREATING A DISORDER related to the RAS protein in a subject in need thereof, the method characterized by comprising administering to the subject a therapeutically effective amount of a RAS(ON) GTP hydrolysis-promoting compound and a RAS(OFF) inhibitor, wherein the RAS does not comprise a RAS mutation at position 61.

14. METHOD FOR INHIBITING RAS ACTIVITY IN A CELL, the method characterized by comprising contacting the cell with an effective amount of a RAS(ON) GTP hydrolysis-promoting compound and a RAS(OFF) inhibitor, wherein the RAS(ON) GTP hydrolysis-promoting compound synergistically increases the cell's sensitivity to the RAS(OFF) inhibitor.

15. METHOD FOR INCREASING THE SENSITIVITY OF A CELL to a RAS(OFF) inhibitor, the method characterized by comprising contacting the cell with an effective amount of a RAS(ON) GTP hydrolysis-promoting compound, wherein the RAS(ON) GTP hydrolysis-promoting compound synergistically increases the sensitivity of the cell to the RAS(OFF) inhibitor.

16. METHOD, according to any one of claims 1 and 6 to 15, characterized in that the RAS(OFF) inhibitor is a KRAS(OFF) inhibitor.

17. METHOD, according to claim 16, characterized in that the KRAS(OFF) inhibitor is a KRASG12C(OFF) inhibitor.

18. METHOD, according to claim 16, characterized in that the KRAS(OFF) inhibitor is a KRASG12D(OFF) inhibitor.

19. METHOD, according to claim 16, characterized in that the KRAS(OFF) inhibitor is a KRASG12V(OFF) inhibitor.

20. METHOD, according to claim 16, characterized in that the KRAS(OFF) inhibitor is a pan-RAS(OFF) inhibitor.

21. METHOD FOR TREATING RASOPATHY in a subject in need thereof, the method characterized by comprising administering to the subject a therapeutically effective amount of a RAS(ON) GTP hydrolysis-promoting compound.

22. METHOD FOR INCREASING THE CROSSLINKING RATE OF A KRASG12C(OFF) INHIBITOR to the cysteine ​​residue at position 12 of KRASG12C in a cell, characterized by comprising contacting the cell with an effective amount of a RAS(ON) GTP hydrolysis-promoting compound.

23. METHOD, according to any one of claims 1 to 22, characterized by the binding of the RAS(ON) GTP hydrolysis-promoting compound to RAS(ON) altering the position of glutamine 61 of RAS(ON), relative to the position in the absence of the RAS(ON) GTP hydrolysis-promoting compound, towards the gamma phosphate of GTP bound to the RAS(ON) protein, thereby increasing the rate of GTP hydrolysis relative to the rate of RAS(ON) hydrolysis in the absence of the RAS(ON) GTP hydrolysis-promoting compound.

24. METHOD, according to any one of claims 1 to 23, characterized in that the RAS(ON) GTP hydrolysis promoting compound is a compound from Table 1 or a pharmaceutically acceptable salt thereof.

25. PHARMACEUTICAL COMPOSITION, characterized by comprising a therapeutically effective amount of a RAS(ON) GTP hydrolysis promoter compound and a RAS(OFF) inhibitor.

26. KIT, characterized by comprising: a) a RAS(ON) GTP hydrolysis promoter compound; and b) a RAS(OFF) inhibitor. Petition 870250108725, dated 11 / 27 / 2025, pp. 350 / 351

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