Inhibition of RAS function through targeting an allosteric regulatory site.

ABSTRACT: RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1. NS1 bound the ?4-?6-?5 region of RAS, which disrupted RAS dimerization and nanoclustering and led to blocking of CRAF-BRAF heterodimerization and activation. These results establish the importance of the ?4-?6-?5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.

SUBMITTER: Spencer-Smith R 

PROVIDER: S-EPMC5193369 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature