A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling

作者：Athuluri Divakar Sai Krishna; Vasquez Del Carpio Rodrigo; Dutta Kaushik; Baker Stacey J; Cosenza Stephen C; Basu Indranil; Gupta Yogesh K; Reddy M V Ramana; Ueno Lynn; Hart Jonathan R; Vogt Peter K; Mulholland David; Guha Chandan; Aggarwal Aneel K; Reddy E Premkumar^*

来源：Cell, 2016, 165(3): 643-655.

DOI：10.1016/j.cell.2016.03.045

Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.

• 出版日期2016-4-21