Upadhyaya Punit, Bedewy Walaa, Pei Dehua
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States.
Mini Rev Med Chem. 2016;16(5):376-82. doi: 10.2174/1389557515666151001141713.
Activating Ras mutations are associated with ~30% of all human cancers, which often respond poorly to standard therapies. The four Ras isoforms are therefore highly attractive targets for anticancer drug discovery. However, Ras proteins function through protein-protein interactions and their surfaces lack any major pockets for small molecules to bind; as a result they have been declared "undruggable" for the past 30 years. Several breakthroughs during the past few years may finally remove Ras from the list of undruggable proteins. This mini-review discusses the current approaches to developing inhibitors especially cyclic peptides that physically block the interaction between Ras and its downstream effector proteins, which is potentially the most effective approach for treating Ras mutant cancers.
激活型Ras突变与约30%的人类癌症相关，这些癌症通常对标准疗法反应不佳。因此，四种Ras亚型是抗癌药物研发的极具吸引力的靶点。然而，Ras蛋白通过蛋白质-蛋白质相互作用发挥功能，其表面缺乏可供小分子结合的主要口袋；因此，在过去30年里，它们被宣布为“不可成药”。过去几年的几项突破可能最终将Ras从不可成药蛋白列表中移除。本综述讨论了目前开发抑制剂的方法，特别是环肽，它们可物理性阻断Ras与其下游效应蛋白之间的相互作用，这可能是治疗Ras突变型癌症最有效的方法。
