Allosteric MEK inhibitors act on BRAF/MEK complexes to block MEK activation.

ABSTRACT: The RAF/MEK/ERK pathway is central to the control of cell physiology, and its dysregulation is associated with many cancers. Accordingly, the proteins constituting this pathway, including MEK1/2 (MEK), have been subject to intense drug discovery and development efforts. Allosteric MEK inhibitors (MEKi) exert complex effects on RAF/MEK/ERK pathway signaling and are employed clinically in combination with BRAF inhibitors in malignant melanoma. Although mechanisms and structures of MEKi bound to MEK have been described for many of these compounds, recent studies suggest that RAF/MEK complexes, rather than free MEK, should be evaluated as the target of MEKi. Here, we describe structural and biochemical studies of eight structurally diverse, clinical-stage MEKi to better understand their mechan

SUBMITTER: Gonzalez-Del Pino GL 

PROVIDER: S-EPMC8433572 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature