The RAS-Effector Interaction as a Drug Target.
The RAS-Effector Interaction as a Drug Target.
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RAS-效应器相互作用作为药物靶点。
DOI：
10.1158/0008-5472.can-16-0938
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发表时间：
2017-01-15
期刊：
影响因子：
11.2
通讯作者：
Piazza GA
中科院分区：
文献类型：
--
作者：
Keeton AB;Salter EA;Piazza GA
大约三分之一的人类癌症在K-，N-或HRAS基因中的一个中含有突变，这些基因编码锁定在组成性激活状态的异常RAS蛋白，以驱动恶性转化和肿瘤生长。尽管有超过三十年的深入研究，旨在发现RAS导向的治疗方法，但没有FDA批准的药物对RAS驱动的癌症广泛有效。虽然RAS蛋白通常被认为是“不可治疗的”，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。在这里，我们审查了这一证据，重点是能够抑制RAS蛋白与其效应子的相互作用，抑制RAS信号，驱动和维持恶性转化和肿瘤生长的化合物。这些直接作用的RAS抑制剂的报告为进一步发现和开发涉及RAS基因突变或以其他方式激活的RAS蛋白的RAS驱动的癌症的临床候选物提供了有价值的见解。
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. While 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 which 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.