AMG410 is a non-covalent, dual-modality KRAS inhibitor effective against both GDP (OFF) and GTP (ON) binding, with Kd (GDP) of 1 nM and Kd (GTP) of 22 nM, capable of blocking KRAS independently of the cell cycle. AMG410 does not affect HRAS and NRAS2, and exhibits high potency against KRAS G12D, G12V, G12C, G13D, and other mutants, with an IC₅₀ of 1–4 nM. It induces tumour regression and reduces phosphorylated ERK levels in KRAS-mutant cancer models.

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

Method:
The inhibitory activity of AMG410 against various KRAS mutants was evaluated, along with its selectivity in different cell types and its binding affinity to KRAS-GTP and KRAS-GDP.

Result:
AMG410 exhibited potent inhibition of KRAS G12D, G12V, and G13D mutants (IC₅₀ = 1–4 nM), with a median IC₅₀ of 12 nM in KRAS-mutant tumor cells, and showed weak inhibition in non-transformed cells (IC₅₀ > 5 μM), indicating high selectivity. It bound both GTP- and GDP-bound KRAS (KD = 22 nM and 1 nM, respectively), enabling state-independent blockade of KRAS signaling.[1]