RMC-8839 (RMC8839) is a potent, selective, covalent and orally active RAS(ON) G13C tri-complex inhibitor with biochemical Kinact of 2.83 x 10-3 s-1 and Ki of 28.3 nM.
RMC-8839 inhibits KRASG13C more potently than wild type RAS in a cellular RAS-RAF1 RBD disruption assay, and more potently inhibits pERK and cell proliferation in a cell line harboring a KRASG13C mutation (NCI-H1734) compared to an EGFR-mutant, RASWT cell line (NCI-H1975).
RMC-8839 is 22- to 311-fold selective for KRASG13C over wild-type RAS.
RMC-8839 is ~6x selective for G13C over G12C as this mutation retains a cysteine residue that can be covalently targeted, but is 20 to >100x selective for G13C all other KRAS mutants.
RMC-8839 covalently modifies KRASG13C while retaining the same protein-protein contacts between RAS and CypA.
(100 mg/kg, oral) demonstrated rapid and durable activity achieving tumor target engagement in mice bearing NCI-H1734 (KRASG13C, NSCLC) xenograft tumors, induced RAS-MAPK pathway suppression reached >95%, exhibited great tumor growth inhibition leading to tumor stasis.
Combination of RMC-8839 and RAS(ON) multi-selective inhibitor daraxonrasib resulted in strong pathway suppression and deep and durable tumor regressions in KRASG13C mutant NCI-H1734 xenograft models.