UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA and Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Biochem J. 2019 Jan 31;476(2):365-374. doi: 10.1042/BCJ20170441.
RAS proteins have traditionally been deemed undruggable, as they do not possess an active site to which small molecules could bind but small molecules that target one form of oncogenic RAS, KRAS G12C, are already in preclinical and clinical trials, and several other compounds that bind to different RAS proteins at distinct sites are in earlier stage evaluation. KRAS is the major clinical target, as it is by far the most significant form of RAS in terms of cancer incidence. Unfortunately, KRAS exists in two isoforms, each with unique biochemical properties. This complicates efforts to target KRAS specifically. KRAS is also a member of a family of closely related proteins, which share similar effector-binding regions and G-domains, further increasing the challenge of specificity. Nevertheless, progress is being made, driven by new drug discovery technologies and creative science.
RAS 蛋白一直被认为是不可成药的，因为它们没有可供小分子结合的活性位点，但靶向一种致癌 RAS 形式（KRAS G12C）的小分子已经在临床前和临床试验中，还有几种其他靶向不同 RAS 蛋白的小分子在早期评估阶段。KRAS 是主要的临床靶点，因为它是迄今为止在癌症发病率方面最重要的 RAS 形式。不幸的是，KRAS 存在两种同工型，每种同工型都具有独特的生化特性。这使得针对 KRAS 进行特异性靶向的努力变得复杂。KRAS 也是一个密切相关的蛋白质家族的成员，它们具有相似的效应器结合区域和 G 结构域，这进一步增加了特异性的挑战。尽管如此，由于新的药物发现技术和创造性的科学，已经取得了进展。
