RMC-6236

RMC-6236 is a non-covalent inhibitor of GTP-bound RAS.¹ It binds to peptidyl-prolyl cis-trans isomerase A (PPIase A), also known as cyclophilin A (CypA; K_d = 55.3 nM) to form a binary complex that then binds to wild-type K-Ras, K-Ras(G12V), and K-Ras(G12D) (K_ds = 131, 364, and 154 nM, respectively). RMC-6236 forms a trimeric complex with PPIase A and a K-Ras, H-Ras, N-Ras, or mutant Ras variant and disrupts the protein-protein interaction between these Ras variants and the B-RAF Ras-binding domain (IC₅₀s = 28-220 nM). It induces apoptosis in 28 K-Ras(G12X) and five N-Ras(Q61X) mutant cancer cell lines when used at concentrations ranging from 1 to 100 nM. In vivo, RMC-6236 (25 mg/kg) inhibits intratumoral ERK phosphorylation and reduces tumor volume in Capan-2 and NCI H441 pancreatic ductal adenocarcinoma (PDAC) mouse xenograft models. It also reduces tumor growth in 29 non-small cell lung cancer (NSCLC), 22 PDAC, and 23 colorectal cancer K-Ras(G12X) mutant mouse xenograft models when administered at a dose of 25 mg/kg.

References:
[1]. Jiang, J., Jiang, L., Maldonato, B.J., et al.Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-driven cancersCancer Discov.14(6)994-1017(2024).