KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients^{1,2,3,4,5,6,7}. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.

KRAS 是癌症中最常见的突变蛋白之一，直接抑制其功能的努力已经持续了几十年。其中最成功的是共价等位基因特异性抑制剂的开发，这些抑制剂将 KRAS G12C 捕获在其非活性构象中并抑制患者的 ^{1,2,3,4,5,6,7} 肿瘤生长。非活性状态选择性抑制是否可用于治疗性靶向非 G12C KRAS 突变体仍在研究中。在这里，我们报道了一种非共价抑制剂的发现和表征，该抑制剂优先结合且具有高亲和力，同时保留 NRAS 和 HRAS。虽然仅限于几个氨基酸，但 RAS 亚型 GTP 酶结构域的进化分歧足以赋予 KRAS 选择性的正构和变构限制。抑制剂阻断核苷酸交换以防止野生型 KRAS 和多种 KRAS 突变体的激活，包括 G12A/C/D/F/V/S、G13C/D、V14I、L19F、Q22K、D33E、Q61H、K117N 和 A146V/T。下游信号传导和增殖的抑制仅限于携带突变型 KRAS 的癌细胞，药物治疗抑制小鼠 KRAS 突变肿瘤生长， 而不会对动物体重产生不利影响。我们的研究表明，大多数 KRAS 癌蛋白在癌细胞的活性状态和非活性状态之间循环，并且依赖于核苷酸交换进行激活。Pan-KRAS 抑制剂，例如此处描述的抑制剂，具有广泛的治疗意义，值得在 KRAS 驱动的癌症患者中进行临床研究。