RM-046 is an orally active and selective inhibitor of the KRASQ61H(active) ternary complex. It forms a ternary complex with cyclophilin A, binding non-covalently to the active KRASQ61H, blocking the binding of effector molecules through steric hindrance and inhibiting downstream signaling. RM-046 suppresses ERK phosphorylation and cancer cell proliferation, and induces sustained inhibition of the RAS pathway, antitumor activity, and tumor regression in preclinical xenograft models. RM-046 is applicable for research in KRASQ61H mutant cancers.