JP-2026514417-A - Composition for inducing RAS-GTP hydrolysis and use thereof

Abstract

This disclosure relates to therapies for treating cancer. In particular, this disclosure relates to a method for treating cancer in subjects requiring treatment for cancer, comprising administering to the subject a therapeutically effective amount of a RAS(ON)GTP hydrolysis-promoting compound (which may optionally be administered in combination with additional therapeutic agents (e.g., RAS(OFF) inhibitors, RTK inhibitors, SHP2 inhibitors, or SOS1 inhibitors)), and also relates to a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor(s), a kit comprising the composition, and a method of using the same. [Selection Diagram] None

Inventors

• ノックス、ジョン イー．
• コルトゥン、エレナ エス．
• シーマン、カイル
• トムリンソン、エイダン
• ワイルズ、デイビッド イー．
• クレッグ、ジェームズ

Assignees

• レヴォリューション・メディスンズ，インコーポレイテッド

Dates

Publication Date

20260511

Application Date

20240329

Priority Date

20230330

Claims (20)

1. A method for treating cancer in a subject requiring cancer treatment, 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 contain an RAS mutation at position 61.
2. A method for treating cancer in a subject requiring cancer treatment, wherein the method comprises administering a therapeutically effective amount of a RAS(ON)GTP hydrolysis-promoting compound to the subject.
3. The method according to claim 2, further comprising administering an SHP2 inhibitor or an SOS1 inhibitor.
4. The method according to claim 2, further comprising administering an SHP2 inhibitor, an SOS1 inhibitor, or an RTK inhibitor.
5. The method according to claim 3 or 4, wherein the RAS(ON)GTP hydrolysis-promoting compound and the SHP2 inhibitor or SOS1 inhibitor are administered simultaneously or sequentially.
6. The method according to claim 5, further comprising administering a RAS(OFF) inhibitor.
7. The method according to claim 6, wherein the RAS(OFF) inhibitor is administered simultaneously with or consecutively with the RAS(ON)GTP hydrolysis-promoting compound and/or the SHP2 inhibitor, SOS1 inhibitor, or RTK inhibitor.
8. The method according to any one of claims 1 to 7, wherein the cancer includes an RAS mutation.
9. The method according to claim 8, wherein the RAS mutation is located at position 12 or 13.
10. The method according to any one of claims 1 to 9, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer, or uterine cancer.
11. The method according to any one of claims 1 to 10, further comprising administering additional anti-cancer therapy.
12. The method according to claim 11, wherein the additional anticancer therapy is an EGFR inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, an immune checkpoint inhibitor, a CDK4/6 inhibitor, a HER2 inhibitor, an RTK inhibitor, or a combination thereof.
13. A method for treating RAS protein-related disorders in subjects requiring treatment for such disorders, comprising administering a therapeutically effective amount of a RAS(ON)GTP hydrolysis-promoting compound and a RAS(OFF) inhibitor to the subject, wherein the RAS does not contain an RAS mutation at position 61.
14. A method for inhibiting RAS activity in cells, comprising contacting the cells 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 sensitivity of the cells to the RAS(OFF) inhibitor.
15. A method for increasing the sensitivity of cells to a RAS(OFF) inhibitor, comprising contacting the cells 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 cells to the RAS(OFF) inhibitor.
16. The method according to any one of claims 1 and 6 to 18, wherein the RAS(OFF) inhibitor is a KRAS(OFF) inhibitor.
17. The method according to claim 19, wherein the KRAS (OFF) inhibitor is a KRAS G12C (OFF) inhibitor.
18. The method according to claim 19, wherein the KRAS (OFF) inhibitor is a KRAS G12D (OFF) inhibitor.
19. The method according to claim 19, wherein the KRAS (OFF) inhibitor is a KRAS G12V (OFF) inhibitor.
20. The method according to claim 19, wherein the KRAS(OFF) inhibitor is a pan-RAF(OFF) inhibitor.

Description

Cancer remains one of the most deadly threats to human health. In the United States, cancer affects approximately 1.3 million new cases each year, is the second leading cause of death after heart disease, and accounts for about one in four deaths. RAS (KRAS, NRAS, HRAS) proteins regulate cell proliferation and other cellular functions by converting between a guanosine triphosphate (GTP)-bound "on" state ("RAS(ON)") and a guanosine diphosphate (GDP)-bound "off" state ("RAS(OFF)"). In its active state, RAS is bound to GTP, which is hydrolyzed to inactivate the GDP bond. RAS proteins have a slow intrinsic hydrolysis rate (Non-Patent Literature 1), which is enhanced in the presence of RAS GTPase activating protein (GAP). GDP-bound RAS can be converted to its active state via a slow exchange of GDP to GTP, enhanced by guanine nucleotide exchange factors (GEFs). One way in which oncogenic mutations in RAS increase the amount of GTP-bound RAS protein is by reducing its intrinsic hydrolysis rate and decreasing its sensitivity to GAP-mediated hydrolysis enhancement. Based on these observations, RAS variants were historically thought to be activated "constitutively" in cancer. The amount of active RAS can also increase via the activation of intracellular GEF, which is either due to upstream protein mutations (e.g., mutations in receptor tyrosine kinases) or non-mutagenic mechanisms (e.g., reactivation of adaptive pathways). In either case, elevated GTP-bound RAS levels lead to excessive cell proliferation. Covalent inhibitors of the "off" form of KRAS G12C have shown promising antitumor activity in cancer patients with oncogenic mutations in KRAS. However, therapeutic inhibition of the RAS pathway may prove ineffective in the long run, even if initially effective, potentially leading to hyperactivation of RAS pathway signaling or resistance to RAS (OFF) inhibitors through numerous mechanisms, including reactivation of RAS pathway signaling by disabling naturally occurring negative feedback mechanisms in these pathways. As a result, cancer cells that were initially sensitive to such inhibitors may become resistant. Most KRAS variants are susceptible to inhibitors that preferentially target their inactive state, suggesting that KRAS variants retain the ability to hydrolyze GTP within cancer cells. These findings spur the exploration of pharmacological interventions that enhance GTP hydrolysis by KRAS variants. Therefore, in this technical field, compositions and methods for inducing RAS-GTP hydrolysis are needed. Furthermore, compositions and methods for enhancing the sensitivity of cancer cells to RAS (OFF) inhibitors are also needed. Westcover et al. , Mol Cancer Res (2015) 13(9):1325-1335 This disclosure provides compositions and uses thereof for treating RAS-related diseases or disorders (e.g., cancer), comprising RAS(ON)GTP hydrolysis-promoting compounds. For example, this disclosure provides combination therapies useful for treating cancer, including combinations of RAS(ON)GTP hydrolysis-promoting compounds and additional therapeutic agents (e.g., RAS(OFF) inhibitors or RAS degrading agents targeting the RAS(OFF) state ("RAS(OFF) degrading agents"). In any embodiment of this specification using RAS(OFF) inhibitors, RAS(OFF) degrading agents may be used instead. In some embodiments, the combination includes two or more therapeutic agents in addition to the RAS(ON)GTP hydrolysis-promoting compound (e.g., RAS(OFF) inhibitors and SHP2 inhibitors). In one embodiment, this disclosure is based at least in part on the observation that contacting cancer cells with RAS(ON)GTP hydrolysis-promoting compounds and RAS(OFF) inhibitors results in a synergistic effect in reducing the survival rate of cancer cells. In other embodiments, the Disclosure provides a method for treating cancer in a subject requiring cancer treatment, the method comprising administering to the subject a therapeutically effective amount of a RAS(ON)GTP hydrolytic compound and a RAS(OFF) inhibitor, wherein the cancer does not contain a RAS mutation at position 61. In some embodiments, the cancer contains a RAS mutation (for example, the RAS mutation is located 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 (RAS AMP ). In some embodiments, the RAS AMP is wild-type RAS or mutant RAS. In each of the above embodiments, the binding of the RAS(ON)GTP hydrolysis-promoting compound to RAS GTP (RAS(ON)) shifts the position of glutamine 61 in RAS(ON) toward the gamma phosphate of GTP bound to the RAS(ON) protein, compared to its position in the absence of the RAS(ON)GTP hydrolysis-promoting compound. This increases the GTP hydrolysis rate compared to the hydrolysis rate of RAS(ON) in the absence of the RAS(ON)GTP hydrolysis-promoting compound. In some