ArticleNature chemical biology2026
MEK interactions tune RAF kinase sensitivity to conformation-selective inhibition.
Article in Nature chemical biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
2 citing papers in PubMed.
- High-resolution measurement of ERK activation state reveals determinants of BRAF regulation and drug sensitivity.bioRxiv : the preprint server for biology · 2026Article
- Evolving faster proximity chemistry.Nature chemical biology · 2026Article
Corrections and comments
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Authors and funding
9 authors.
Funding
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.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.