MCB-294 is a potent, selective, dual-state pan-KRAS inhibitor capable of binding both the active (GTP-bound) and inactive (GDP-bound) forms of KRAS, effectively inactivates both wild-type KRAS and multiple KRAS mutants.
MCB-294 broadly impairs the growth of hTERT-HPNE cells expressing G12D, G12C, G12V, G12S, G13D, and wild-type KRAS, with IC50 of approximately 700 nM.
MCB-294 exhibits high-affinity binding to both GDP-bound and GppNHp-bound KRAS, with dissociation constants (Kd) of approximately 1 pM and 10 nM, respectively.
MCB-294 inhibits the binding of SOScat to KRAS proteins in KRAS(GDP)-SOScat HTRF binding assay with IC50 of 1-70 nM.
MCB-294 disrupts RAF-RBD peptide binding to active KRAS, exhibiting IC50s approximately ranging from 20 to 150 nM in KRAS(GppNHp)-RBD HTRF binding assays.
Mutations at binding residues G10 (G10L) and T58 (T58A) significantly attenuates MCB-294's inhibitory effects on both SOScat-KRAS binding (IC50 > 200 nM) and cellular viability.
MCB-294 has minimal effect on HRAS- or NRAS-SOScat binding.
MCB-294 inhibits the growth of KRAS-dependent cancer cells and patient-derived organoids, shows significant anti-proliferative effects on KRAS-dependent cancer cells with mean IC50 of 125 nM, while sparing normal cells.
MCB-294 causes a dose-dependent reduction in p-ERK levels in all tested KRAS-dependent cancer cells but not in KRAS-independent cancer cells and normal cells.
MCB-294 (30 mg/kg, i.p., BID) impedes the growth of KRAS-driven tumors in patient-derived xenograft (PDX) mouse models, inhibits oncogenic KRAS signaling pathways.