2. Academic Validation
  3. MEK interactions tune RAF kinase sensitivity to conformation-selective inhibition

MEK interactions tune RAF kinase sensitivity to conformation-selective inhibition

  • Nat Chem Biol. 2026 May 12:10.1038/s41589-026-02212-2. doi: 10.1038/s41589-026-02212-2.
Ethan G Stoddard 1,  B Gayani K Perera 1,  Linglan Fang 1,  Daniel S Brush 1,  Yuhao Zhong 1,  Zachary E Potter 1,  Jessica J Simon 1,  Martin Golkowski 2 3 4,  Dustin J Maly 5 6
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Washington, Seattle, WA, USA.
  • 2 Department of Pharmacology, University of Washington, Seattle, WA, USA.
  • 3 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
  • 4 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • 5 Department of Chemistry, University of Washington, Seattle, WA, USA. [email protected].
  • 6 Department of Biochemistry, University of Washington, Seattle, WA, USA. [email protected].
PMID: 42120500 DOI: 10.1038/s41589-026-02212-2
Abstract

Raf kinases are key effectors in the RAS-RAF-MEK-ERK signaling pathway, making them important targets for the development of Cancer therapeutics. Here we investigate the variable potency of DFG-out-stabilizing Raf inhibitors in mutant KRAS-expressing cell lines. We demonstrate that inhibitor potency correlates with basal Raf activity, with more active Raf being more sensitive to inhibition. We further show that DFG-out-stabilizing inhibitors disrupt high-affinity RAF-MEK interactions, promoting the formation of inhibited Raf dimers. Furthermore, we identify cobimetinib as an MEK Inhibitor that uniquely sensitizes Raf kinases to DFG-out-stabilizing inhibitors by disrupting autoinhibited RAF-MEK complexes. Building on this insight, we developed cobimetinib analogs with enhanced sensitization properties. Together, our findings provide a mechanistic framework for understanding the cellular determinants of DFG-out-stabilizing inhibitor sensitivity and offer strategies for optimizing synergistic RAF-MEK inhibitor combinations.

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