Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics
Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics
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DOI：
10.1021/acs.jmedchem.0c01312
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发表时间：
2020-12-10
影响因子：
7.3
通讯作者：
Lu, Xiaoyun
中科院分区：
文献类型：
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作者：
Chen, Hao;Smaill, Jeff B.;Lu, Xiaoyun
KRAS是最常突变的癌基因，在驱动癌症的发生和发展中起着主导作用。几十年来，使用小分子靶向KRAS的努力一直不成功，导致KRAS被认为是一种“不可治疗”的癌症靶点。然而，这种观点最近开始改变，因为药物发现技术已经开发出几种KRAS G12 C变构抑制剂，目前正在临床试验中进行评估。在本文中，我们提供了对KRAS的结构和结合口袋的深入分析，药物化学优化过程以及直接靶向KRAS的小分子抑制剂的生物学表征，包括对G12 C突变体特异性的共价变构抑制剂，靶向核苷酸结合位点的GTP竞争性抑制剂，以及结合开关I/II口袋或A59位点的蛋白质-蛋白质相互作用抑制剂。此外，我们提出了这些新类别的KRAS抑制剂在临床评价中面临的潜在挑战。
KRAS, the most frequently mutated oncogene, plays a predominant role in driving initiation and progression of cancers. Decades of effort to target KRAS using small molecules has been unsuccessful, causing KRAS to be considered an "undruggable" cancer target. However, this view began to change recently, as drug discovery techniques have developed several KRAS G12C allosteric inhibitors that are currently being evaluated in clinical trials. Herein we provide an in-depth analysis of the structure and binding pockets of KRAS, medicinal chemistry optimization processes, and the biological characterization of small-molecule inhibitors that directly target KRAS, including covalent allosteric inhibitors specific for the G12C mutant, GTP-competitive inhibitors targeting the nucleotide-binding site, and protein-protein interaction inhibitors that bind in the switch I/II pocket or the A59 site. Additionally, we propose potential challenges faced by these new classes of KRAS inhibitors under clinical evaluation.