小柯机器人

美国纪念斯隆-凯特琳癌症中心Piro Lito团队发现，泛KRAS抑制剂使致癌信号和肿瘤生长失效。相关论文于2023年5月31日在线发表在《自然》杂志上。

研究人员报告了一种非共价抑制剂的发现和表征，它能优先与KRAS的非活性状态结合，并具有高亲和力，同时又不影响NRAS和HRAS。虽然只限于几个氨基酸，但RAS亚型的GTP酶结构域演化差异足以为KRAS的选择性带来正交和异交的限制。该抑制剂阻断了核苷酸交换，阻止了野生型KRAS和广泛的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。下游信号的抑制和增殖仅限于携带突变型KRAS的癌细胞，药物治疗抑制了小鼠KRAS突变型肿瘤的生长，但对动物体重没有不利的影响。这项研究表明，大多数KRAS肿瘤蛋白在癌细胞中的活性状态和非活性状态之间循环，并依赖核苷酸交换来激活。泛KRAS抑制剂，如这项研究描述的抑制剂，具有广泛的治疗意义，值得对KRAS驱动的癌症患者进行临床研究。

据介绍，KRAS是癌症中最常见的突变蛋白之一，几十年来一直在努力直接抑制其功能。其中最成功的是开发共价等位基因特异性抑制剂，将KRAS G12C困在其非活性构象中并抑制患者的肿瘤生长。非活性状态下的选择性抑制是否可用于治疗非G12C KRAS突变体仍在研究中。

附：英文原文

Title: Pan-KRAS inhibitor disables oncogenic signalling and tumour growth

Author: Kim, Dongsung, Herdeis, Lorenz, Rudolph, Dorothea, Zhao, Yulei, Bttcher, Jark, Vides, Alberto, Ayala-Santos, Carlos I., Pourfarjam, Yasin, Cuevas-Navarro, Antonio, Xue, Jenny Y., Mantoulidis, Andreas, Brker, Joachim, Wunberg, Tobias, Schaaf, Otmar, Popow, Johannes, Wolkerstorfer, Bernhard, Kropatsch, Katrin Gabriele, Qu, Rui, de Stanchina, Elisa, Sang, Ben, Li, Chuanchuan, McConnell, Darryl B., Kraut, Norbert, Lito, Piro

Issue&Volume: 2023-05-31

Abstract: 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 patients1,2,3,4,5,6,7. 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.

DOI: 10.1038/s41586-023-06123-3

Source: https://www.nature.com/articles/s41586-023-06123-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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