RMC-6236

RMC-6236 (CAS 2765081-21-6) is a non-covalent inhibitor targeting the GTP-bound state of RAS, with its mechanism of action dependent on the synergistic effect with cyclophilin A (CypA, also known as peptidyl-prolyl cis-trans isomerase A). Initially, RMC-6236 forms a binary complex with CypA with a dissociation constant (KD1) of 55.3 nM. Subsequently, this complex binds to wild-type KRAS and mutant KRAS (G12V, G12D) with dissociation constants (KD2) of 131 nM, 364 nM, and 154 nM, respectively, resulting in the formation of a ternary complex. This complex disrupts the protein-protein interactions between KRAS, HRAS, NRAS (including various RAS mutants) and the Ras-binding domain of BRAF, with half-maximal inhibitory concentrations (IC50) ranging from 28 to 220 nM. At concentrations of 1–100 nM, RMC-6236 induces apoptosis in 28 KRAS (G12X) mutant and 5 NRAS (Q61X) mutant cancer cell lines. In in vivo studies, administration of RMC-6236 at a dose of 25 mg/kg inhibited intratumoral ERK phosphorylation and significantly reduced the tumor volumes of Capan-2 and NCI-H441 pancreatic ductal adenocarcinoma (PDAC) xenografts in mice. Furthermore, RMC-6236 suppressed the growth of 29 non-small cell lung cancer (NSCLC), 22 PDAC, and 23 colorectal cancer xenografts harboring KRAS (G12X) mutations in mouse models.

References:

[1] Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, Winters IP, Salman Z, Blaj C, Menard M, Brodbeck J, Chen Z, Wei X, Rosen MJ, Gindin Y, Lee BJ, Evans JW, Chang S, Wang Z, Seamon KJ, Parsons D, Cregg J, Marquez A, Tomlinson ACA, Yano JK, Knox JE, Quintana E, Aguirre AJ, Arbour KC, Reed A, Gustafson WC, Gill AL, Koltun ES, Wildes D, Smith JAM, Wang Z, Singh M. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov. 2024 Jun 3;14(6):994-1017. doi: 10.1158/2159-8290.CD-24-0027. Erratum in: Cancer Discov. 2025 Oct 6;15(10):2186. doi: 10.1158/2159-8290.CD-25-1519. PMID: 38593348; PMCID: PMC11149917.