Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling.

ABSTRACT: Deregulation of the Ras-mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes. Kinase suppressor of Ras (KSR) is a MAPK scaffold that is subject to allosteric regulation through dimerization with RAF. Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutations that selectively suppress oncogenic, but not wild-type, Ras signalling, we developed a class of compounds that stabiliz

SUBMITTER: Dhawan NS 

PROVIDER: S-EPMC5161575 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature