Structural basis for the action of the drug trametinib at KSR-bound MEK.

ABSTRACT: The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology¹, and more recently in immunotherapy^2,3 and ageing⁴. However, many MEK inhibitors are limited owing to on-target toxicities^5-7 and drug resistance^8-10. Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEK inhibitors, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR

SUBMITTER: Khan ZM 

PROVIDER: S-EPMC7746607 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature