Chuang Hsiao-Ching, Huang Po-Hsien, Kulp Samuel K, Chen Ching-Shih
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Pharmacol Res. 2017 Mar;117:370-376. doi: 10.1016/j.phrs.2017.01.006. Epub 2017 Jan 8.
The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents. Mechanistically, these KRAS-targeted agents can be classified into the following four categories. (1) Small-molecule RAS-binding ligands that prevent RAS activation by binding within or outside the nucleotide-binding motif. (2) Inhibitors of KRAS membrane anchorage. (3) Inhibitors that bind to RAS-binding domains of RAS-effector proteins. (4) Inhibitors of KRAS expression. The advantage and limitation of each type of these anti-KRAS agents are discussed.
突变型KRAS作为治疗靶点的明确重要性推动了人们在不同分子水平上对多种抑制致癌性KRAS信号传导方法的研究。然而，迄今为止尚无针对KRAS的疗法进入临床，这突出了开发有效、直接的KRAS抑制剂的内在困难。因此，本文概述了利用小分子药物靶向致癌性KRAS的药理学策略的发展历史和最新进展。从机制上讲，这些靶向KRAS的药物可分为以下四类。（1）小分子RAS结合配体，通过在核苷酸结合基序内部或外部结合来阻止RAS激活。（2）KRAS膜锚定抑制剂。（3）与RAS效应蛋白的RAS结合域结合的抑制剂。（4）KRAS表达抑制剂。文中讨论了每种抗KRAS药物的优缺点。
