Keeton Adam B, Salter E Alan, Piazza Gary A
Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
ADT Pharmaceuticals Inc., Orange Beach, Alabama.
Cancer Res. 2017 Jan 15;77(2):221-226. doi: 10.1158/0008-5472.CAN-16-0938. Epub 2017 Jan 6.
About a third of all human cancers harbor mutations in one of the K-, N-, or HRAS genes that encode an abnormal RAS protein locked in a constitutively activated state to drive malignant transformation and tumor growth. Despite more than three decades of intensive research aimed at the discovery of RAS-directed therapeutics, there are no FDA-approved drugs that are broadly effective against RAS-driven cancers. Although RAS proteins are often said to be "undruggable," there is mounting evidence suggesting it may be feasible to develop direct inhibitors of RAS proteins. Here, we review this evidence with a focus on compounds capable of inhibiting the interaction of RAS proteins with their effectors that transduce the signals of RAS and that drive and sustain malignant transformation and tumor growth. These reports of direct-acting RAS inhibitors provide valuable insight for further discovery and development of clinical candidates for RAS-driven cancers involving mutations in RAS genes or otherwise activated RAS proteins. Cancer Res; 77(2); 221-6. ©2017 AACR.
大约三分之一的人类癌症中，K、N或HRAS基因之一存在突变，这些基因编码一种异常的RAS蛋白，该蛋白处于持续激活状态，从而驱动恶性转化和肿瘤生长。尽管经过三十多年的深入研究旨在发现针对RAS的治疗方法，但目前尚无美国食品药品监督管理局（FDA）批准的能广泛有效对抗RAS驱动型癌症的药物。虽然RAS蛋白常被认为是“不可成药的”，但越来越多的证据表明开发RAS蛋白的直接抑制剂可能是可行的。在此，我们回顾这一证据，重点关注能够抑制RAS蛋白与其效应器相互作用的化合物，这些效应器转导RAS信号并驱动和维持恶性转化及肿瘤生长。这些关于直接作用的RAS抑制剂的报道为进一步发现和开发针对RAS驱动型癌症的临床候选药物提供了有价值的见解，这些癌症涉及RAS基因突变或以其他方式激活的RAS蛋白。《癌症研究》；77(2)；221 - 226。©2017美国癌症研究协会（AACR）
