AMG410 is a non-covalent, bimodal GDP (OFF) and GTP (ON)-binding pan-KRAS inhibitor with Kd (GDP) = 1 nM and Kd (GTP) = 22 nM, which enables circulation-independent blockade of KRAS. AMG410 is more than 100-fold selective for KRAS than HRAS and NRAS2, binds on the same variegated pocket as KRAS G12C inhibitors, and has high potency in KRAS G12D, G12V, G12C, G13D and other mutants, IC 50 = 1-4 nM. AMG140 regresses tumors and reduces phosphorylated ERK levels in colorectal, pancreatic and lung models of KRAS mutations.

KRas (G12V): 1-4 nM, KRas (G12D): 1-4 nM, KRAS (G13D): 1-4 nM

AMG410 is a non-covalent pan-KRAS inhibitor that demonstrates potent activity against several clinically relevant KRAS mutations, including G12D, G12V, and G13D, with IC₅₀ values ranging from 1 to 4 nM. AMG410 exhibits strong antiproliferative effects in KRAS-mutant cancer cells (median IC₅₀ = 12 nM), while showing minimal activity in non-KRAS-transformed cells (IC₅₀ > 5 μM), indicating excellent selectivity. AMG 410 binds both the GTP-bound (active) and GDP-bound (inactive) states of KRAS (KD = 22 nM and 1 nM, respectively), enabling state-independent inhibition of KRAS signaling[1].