Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view

摘要: Ras proteins are small GTPases, cycling between inactive GDP-bound and active GTP-bound states. Through these switches they regulate signaling that controls cell growth proliferation. Activating mutations associated with approximately 30% of human cancers, which frequently resistant to standard therapies. Over the past few years, structural biology in silico drug design, coupled improved screening technology, led a handful promising inhibitors, raising possibility drugging proteins. At same time, invariable emergence resistance argues for critical importance additionally honing on pathways likely be involved. Here we overview current advances knowledge, including conformational dynamic full-length solution at membrane, therapeutic inhibition activity by targeting its site, allosteric sites, Ras–effector protein–protein interfaces, dimers, K-Ras4B/calmodulin/PI3Kα trimer, siRNA. To mitigate resistance, propose can co-targeted along explain why. These include leading expression (or activation) YAP1 c-Myc. We postulate pathways, MAPK/ERK PI3K/Akt/mTOR, act independently corresponding ways cycle control. The data instrumental discovery development inhibitors treating RAS-driven cancers. Together blueprints through evolve, this review provides comprehensive innovative master plan tackling mutant