RMC-6236
[CAS# 2765081-21-6]

Identification

• Classification: Biochemical >> Inhibitor >> G protein coupled receptor(GPCR & G Protein)
• Name: RMC-6236
• Synonyms: Ras-IN-2; (1S,2S)-N-[(7S,13S)-21-ethyl-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.12,5.19,13.022,26]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methylcyclopropane-1-carboxamide
• Molecular Formula: C₄₄H₅₈N₈O₅S
• Molecular Weight: 811.05
• CAS Registry Number: 2765081-21-6
• SMILES: CCN1C2=C3C=C(C=C2)C4=CSC(=N4)C[C@@H](C(=O)N5CCC[C@H](N5)C(=O)OCC(CC3=C1C6=C(N=CC(=C6)N7CCN(CC7)C)[C@H](C)OC)(C)C)NC(=O)[C@H]8C[C@@H]8C

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Index of refraction: 1.688 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319
• Precautionary Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovory and Applicatios

RMC-6236 is an investigational, orally bioavailable small-molecule inhibitor developed by Revolution Medicines. It is designed to selectively target the active, GTP-bound form of RAS proteins, including both mutant and wild-type variants of the canonical RAS isoforms: KRAS, NRAS, and HRAS. This compound represents a novel approach in targeting RAS-driven cancers, which constitute a significant portion of human malignancies.

Preclinical studies have demonstrated that RMC-6236 exhibits potent anticancer activity across various RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. In vivo experiments have shown that oral administration of RMC-6236 leads to significant tumor regressions in multiple tumor types, including models of pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). These findings suggest that RMC-6236 effectively inhibits RAS signaling pathways, resulting in reduced tumor growth and enhanced apoptosis in RAS-mutant cancers.

Clinically, RMC-6236 is undergoing evaluation in a multicenter, Phase 1/1b open-label study (NCT05379985) to assess its safety, tolerability, pharmacokinetics, and clinical activity in adult patients with advanced solid tumors harboring specific RAS mutations. The study aims to determine the maximum tolerated dose and/or recommended Phase 2 dose within the investigated patient population groups. As of September 30, 2024, a total of 436 patients were treated across NSCLC (n=132) and PDAC and other solid tumors (n=304) cohorts, with doses ranging from 10 mg to 400 mg once daily.

In the PDAC cohort, patients with KRAS G12X mutations treated with 300 mg of RMC-6236 once daily achieved a median progression-free survival (PFS) of 8.8 months, while the median overall survival (OS) was not estimable at the time of reporting. The objective response rate (ORR) in this subgroup was 36%. These results indicate that RMC-6236 demonstrates compelling antitumor activity in patients with previously treated PDAC harboring KRAS G12X mutations.

In the NSCLC cohort, patients with previously treated RAS mutant NSCLC who received RMC-6236 at clinically active doses (120 mg to 300 mg once daily) exhibited a median PFS of 9.8 months and a median OS of 17.7 months. The ORR in this population was 38%. These findings suggest that RMC-6236 is effective in treating NSCLC patients with RAS mutations, providing a potential therapeutic option for this patient group.

RMC-6236 has generally been well tolerated across different dose levels. The most common treatment-related adverse events (TRAEs) were rash and gastrointestinal-related toxicities, primarily Grade 1 or 2 in severity. No Grade 3 or higher TRAEs were observed in greater than 10% of patients. Importantly, there were no treatment discontinuations due to TRAEs, and the mean dose intensity was 89%, indicating a favorable safety profile.

In addition to monotherapy, RMC-6236 is being evaluated in combination with other therapeutic agents. For instance, the combination of RMC-6236 with pembrolizumab, an immune checkpoint inhibitor, is under investigation in patients with RAS mutant NSCLC. Preliminary data suggest that this combination is generally well tolerated, with a safety profile consistent with previously reported results for the individual agents. Furthermore, RMC-6236 is being studied in combination with RMC-6291, a RAS(ON) G12C-selective inhibitor, in patients with RAS G12C mutant solid tumors. Early findings indicate that this combination is also well tolerated and may offer therapeutic benefits in this patient population.

Based on the encouraging clinical data, Revolution Medicines is advancing RMC-6236 into pivotal Phase 3 trials. The RASolute 302 study is a randomized Phase 3 trial comparing RMC-6236 to standard-of-care chemotherapy in second-line patients with previously treated metastatic PDAC. Additionally, the RASolve 301 study is a randomized Phase 3 trial evaluating RMC-6236 versus docetaxel in patients with previously treated, locally advanced or metastatic RAS mutant NSCLC. These studies aim to further assess the efficacy and safety of RMC-6236 in larger patient populations and potentially support its approval as a novel therapeutic option for RAS-driven cancers.

In summary, RMC-6236 is a promising investigational agent targeting the active form of RAS proteins, showing significant antitumor activity and a favorable safety profile in early clinical studies. Its continued development in monotherapy and combination regimens holds potential for addressing the unmet medical needs of patients with RAS-mutant cancers.

References

2024. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discovery, 14(6).
DOI: 10.1158/2159-8290.cd-24-0027