Inhibition of RAS: proven and potential vulnerabilities.
Inhibition of RAS: proven and potential vulnerabilities.
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DOI：
10.1042/bst20190023
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发表时间：
2020-10-30
影响因子：
3.9
通讯作者：
O'Bryan JP
中科院分区：
文献类型：
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作者：
Zuberi M;Khan I;O'Bryan JP
RAS是一种在人类癌症中经常发生突变的膜定位小GTPase。因此，自近40年前RAS被发现以来，它一直是开发癌症治疗方法的重点目标。然而，由于明显缺乏易于识别的结合小分子抑制剂的深层口袋，直接靶向RAS的努力一直具有挑战性，导致许多人认为RAS是不可药物的。最近，针对KRAS中突变体Cys残基（G12C）的共价抑制剂的突破性发现，实现了直接抑制RAS的一个重要里程碑。令人惊讶的是，这些g12c反应性化合物仅针对处于gdp结合状态的突变体RAS，从而将其锁定在非活性构象中，并阻断其与下游效应途径偶联的能力。在这一成功的基础上，几个研究小组已经开发出了选择性靶向KRAS（G12C）的类似化合物，其中AMG510和MRTX849率先进入临床试验。两者都显示出了初步的可喜结果。尽管这些化合物的成功重新点燃了直接药理抑制RAS的可能性，但这些共价抑制剂仅限于治疗KRAS（G12C）肿瘤，而KRAS（G12C）肿瘤占人类肿瘤中所有RAS突变体的15%以下。因此，鉴定更广泛有效的RAS抑制剂的需求仍未得到满足。在这里，我们将讨论RAS（G12C）抑制剂的现状以及通过靶向RAS二聚化抑制其他RAS突变体的潜力，RAS二聚化已成为RAS功能变构调节的重要步骤。
RAS is a membrane localized small GTPase frequently mutated in human cancer. As such, RAS has been a focal target for developing cancer therapeutics since its discovery nearly four decades ago. However, efforts to directly target RAS have been challenging due to the apparent lack of readily discernable deep pockets for binding small molecule inhibitors leading many to consider RAS as undruggable. An important milestone in direct RAS inhibition was achieved recently with the groundbreaking discovery of covalent inhibitors that target the mutant Cys residue in KRAS(G12C). Surprisingly, these G12C-reactive compounds only target mutant RAS in the GDP-bound state thereby locking it in the inactive conformation and blocking its ability to couple with downstream effector pathways. Building on this success, several groups have developed similar compounds that selectively target KRAS(G12C), with AMG510 and MRTX849 the first to advance to clinical trials. Both have shown early promising results. Though the success with these compounds has reignited the possibility of direct pharmacological inhibition of RAS, these covalent inhibitors are limited to treating KRAS(G12C) tumors which account for <15% of all RAS mutants in human tumors. Thus, there remains an unmet need to identify more broadly efficacious RAS inhibitors. Here, we will discuss the current state of RAS(G12C) inhibitors and the potential for inhibiting additional RAS mutants through targeting RAS dimerization which has emerged as an important step in the allosteric regulation of RAS function.