在约30%的人类癌症中发现激活Ras突变。ras激活受鸟嘌呤核苷酸交换因子调控,比如七胎之子(SOS),它们与Ras形成蛋白质-蛋白质相互作用(PPI),并催化GTP交换GDP。这是Ras活化中的限速步骤。然而,Ras表面缺乏任何明显的合适的口袋,分子可能会紧密地结合在一起,使Ras蛋白质在超过30年的时间里仍然“不可用”。替代方法之一是设计靶向Ras-SOSPPI界面的抑制剂,一种治疗Ras突变癌症的策略正在获得越来越多的认可。在本文中,我们关注在过去几年中积累的与针对Ras-SOSPPI界面的小分子调节剂或肽模拟物的设计有关的数据。我们强调,然而,即使这种Ras-SOS疗法是有效的,可能出现耐药性。为了抵消这种发展,我们提出了“途径药物鸡尾酒”,也就是说,针对平行(或代偿)途径的药物组合。一系列分类癌症,细胞/组织,和途径/蛋白质组合将有利于这一目标。
Activating Ras mutations are found in about 30 % of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein-protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate-limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still \'undruggable\' for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras-SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small-molecule modulators or peptide mimetics aimed at the interface of the Ras-SOS PPI. We emphasize, however, that even if such Ras-SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose \"pathway drug cocktails\", that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal.