ArticleProceedings of the National Academy of Sciences of the United States of America2021
Allosteric MEK inhibitors act on BRAF/MEK complexes to block MEK activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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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
48 citing papers in PubMed, 82 citations in OpenAlex.
- Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2025Trial
- Longitudinal Genomic Analysis to Fine-tune Targeted Therapy: Results of the Phase II LOGIC 2 Trial in Patients with BRAFV600-Mutant Metastatic Melanoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Comprehensive genomic profiling of mucosal melanoma reveals novel fusion transcripts and dysregulation of cell-cycle, MAPK, and PI3K pathways.The Journal of pathology · 2026Article
- Langerhans cell histiocytosis: molecular mechanisms underlying pathogenesis and emerging targeted therapeutics.Cancer metastasis reviews · 2026Review
- Spatial biology of crowded tumor cells: A new map for designing drug combinations.Current opinion in structural biology · 2026Review
- Chromobox 2 Inhibition: A Novel Activity of Alisertib, an Aurora A Kinase Inhibitor.Molecular cancer therapeutics · 2026Article
- A conserved dimerization element is required for protein kinase activation bybioRxiv : the preprint server for biology · 2026Article
- MEK interactions tune RAF kinase sensitivity to conformation-selective inhibition.Nature chemical biology · 2026Article
- A multi-target drug design method based on target feature fusion.BMC bioinformatics · 2026Article
- Insights into Molecular Mechanisms of Polyphenolic Compounds fromPharmaceuticals (Basel, Switzerland) · 2026Article
- Induced proximity-based therapeutic modalities.Nature reviews. Drug discovery · 2026Review
- Pre-assembled complexes and allosteric effects: parallels between eukaryotic phosphorylation cascades and membrane fusion during herpesviral entry.Journal of virology · 2026Review
- CAPG serves as a prognostic biomarker and promotes proliferation and migration in pancreatic ductal adenocarcinoma.PloS one · 2026Article
- Case Report: Schwann cell reprogramming and PDGF-driven nerve hypertrophy in an NF1 patient with CIDP-like autoimmunity.Frontiers in immunology · 2026Article
- A molecular glue halts RAS-MAPK signaling.Nature cancer · 2026Article
- RAF isoform selectivity of MEK inhibitors and rational design of a covalent ARAF-MEK inhibitor.bioRxiv : the preprint server for biology · 2025Article
- Uncovering the molecular basis of kinase activity and substrate recognition with phospho-PCA.bioRxiv : the preprint server for biology · 2025Article
- Cryo-EM structures of CRAF/MEK1/14-3-3 complexes in autoinhibited and open-monomer states reveal features of RAF regulation.Nature communications · 2025Article
- Myalgia and Rigidity as Adverse Effects of Trametinib Therapy.The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG · 2025Article
- Capacity for Compensatory Cyclin D2 Response Confers Trametinib Resistance in Canine Mucosal Melanoma.Cancers · 2025Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
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 mechanism of action on BRAF/MEK complexes. We find that all of these agents bind in the MEK allosteric site in BRAF/MEK complexes, in which they stabilize the MEK activation loop in a conformation that is resistant to BRAF-mediated dual phosphorylation required for full activation of MEK. We also show that allosteric MEK inhibitors act most potently on BRAF/MEK complexes rather than on free active MEK, further supporting the notion that a BRAF/MEK complex is the physiologically relevant pharmacologic target for this class of compounds. Our findings provide a conceptual and structural framework for rational development of RAF-selective MEK inhibitors as an avenue to more effective and better-tolerated agents targeting this pathway.
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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.