RM-036

RM-036 is a first-in-class, orally bioavailable, tri-complex covalent inhibitor designed to target the active (GTP-bound) state of the KRASG12D mutant protein. Developed by Revolution Medicines, the compound utilizes a unique "tri-complex" mechanism where it forms a ternary complex with the abundant intracellular chaperone cyclophilin A (CypA) and the active state of KRASG12D. This interaction positions a covalent warhead to selectively engage the aspartic acid residue at position 12 of the mutant KRAS protein, which is typically difficult to target due to its low reactivity. By inhibiting the active state of KRASG12D, RM-036 effectively suppresses downstream oncogenic signaling in the RAS pathway. Preclinical studies presented at AACR 2022 demonstrated that RM-036 induces deep and durable tumor regressions in various KRASG12D-mutant xenograft models, including those for pancreatic, colorectal, and non-small cell lung cancers.