NCI-Ras Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Maryland 21702.
Cold Spring Harb Perspect Med. 2018 Jul 2;8(7):a031864. doi: 10.1101/cshperspect.a031864.
The high prevalence of KRAS mutations in human cancers and the lack of effective treatments for patients ranks KRAS among the most highly sought-after targets for preclinical oncologists. Pharmaceutical companies and academic laboratories have tried for decades to identify small molecule inhibitors of oncogenic KRAS proteins, but little progress has been made and many have labeled KRAS undruggable. However, recent progress in in silico screening, fragment-based drug design, disulfide tethered screening, and some emerging themes in RAS biology have caused the field to reconsider previously held notions about targeting KRAS. This review will cover some of the historical efforts to identify RAS inhibitors, and some of the most promising efforts currently being pursued.
KRAS 基因突变在人类癌症中的高发生率和缺乏针对患者的有效治疗方法，使 KRAS 成为临床前肿瘤学家最受关注的目标之一。制药公司和学术实验室数十年来一直试图确定致癌性 KRAS 蛋白的小分子抑制剂，但进展甚微，许多人将 KRAS 标记为不可成药。然而，最近在计算机筛选、基于片段的药物设计、二硫键连接筛选以及 RAS 生物学中的一些新兴主题方面的进展，促使该领域重新考虑以前针对 KRAS 的概念。本文综述了一些鉴定 RAS 抑制剂的历史努力，以及目前正在进行的一些最有希望的努力。
