Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, U.S.A.
Ralph H. Johnson VA Medical Center, Charleston, SC 29401, U.S.A.
Biochem Soc Trans. 2020 Oct 30;48(5):1831-1841. doi: 10.1042/BST20190023.
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.
RAS 是一种位于细胞膜上的小 GTPase，在人类癌症中经常发生突变。因此，自近四十年前发现以来，RAS 一直是开发癌症治疗药物的焦点目标。然而，由于明显缺乏可识别的小分子抑制剂结合的深口袋，直接靶向 RAS 的努力一直具有挑战性，这使得许多人认为 RAS 不可成药。最近，通过突破性地发现靶向 KRAS(G12C)中突变 Cys 残基的共价抑制剂，直接 RAS 抑制取得了重要的里程碑。令人惊讶的是，这些 G12C 反应性化合物仅靶向 GDP 结合状态下的突变 RAS，从而将其锁定在无活性构象中并阻止其与下游效应途径偶联的能力。在此成功的基础上，几个小组已经开发了类似的化合物，这些化合物选择性地靶向 KRAS(G12C)，其中 AMG510 和 MRTX849 是首批进入临床试验的化合物。两者都显示出早期有希望的结果。尽管这些化合物的成功重新点燃了直接药理学抑制 RAS 的可能性，但这些共价抑制剂仅限于治疗 KRAS(G12C)肿瘤，这些肿瘤占人类肿瘤中所有 RAS 突变体的<15%。因此，仍然需要确定更广泛有效的 RAS 抑制剂。在这里，我们将讨论当前 RAS(G12C)抑制剂的状态，以及通过靶向 RAS 二聚化来抑制其他 RAS 突变体的潜力，这已成为 RAS 功能变构调节中的一个重要步骤。
