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

AMG410 是一种非共价 pan-KRAS 抑制剂，针对多种 KRAS 突变体（如 G12D、G12V、G13D）展现出强效抑制活性，IC₅₀ 范围为 1–4 nM。在 KRAS 突变肿瘤细胞中，AMG410中位 IC₅₀ 为 12 nM，而在非 KRAS 转化细胞中抑制作用极弱（IC₅₀ > 5 μM），显示出优异的选择性。AMG 410 同时结合 KRAS 的 GTP 和 GDP 状态（KD 分别为 22 nM 和 1 nM），可实现状态无关的 KRAS 信号阻断[1]。