ReviewBiochemical Society transactions2021
Inhibition of RAF dimers: it takes two to tango.
Review in Biochemical Society transactions, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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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
49 citing papers in PubMed, 93 citations in OpenAlex.
- Encorafenib plus binimetinib for BRAF V600E-mutant metastatic NSCLC: clinical implications of the phase 2 PHAROS study.Future oncology (London, England) · 2024Trial
- RAF1 scaffold integrity shapes chemogenetic degradation outcomes in KRAS-driven lung cancer models.Life science alliance · 2026Article
- Acyclic Retinoid Attenuates STAT3 Signaling and Reduces In Vitro Growth of A375-Derived Dabrafenib Plus Trametinib-Resistant Melanoma Cells.International journal of molecular sciences · 2026Article
- An inhibitor of GCN2 and the integrated stress response directly targets ZAK protein kinase to limit cytotoxicity.The Journal of biological chemistry · 2026Article
- Cryo-EM structure and biochemical characterization of a BRAF/CRAF heterodimer: Negative charge in the NtA motif is not required for RAF activation.bioRxiv : the preprint server for biology · 2026Article
- A Scalable Sign-Aware Multi-Omics Knowledge Graph Foundation Model for Mechanistic Drug Action and Clinical Response Predictions.bioRxiv : the preprint server for biology · 2026Article
- Advances in BRET probes for intracellular target engagement studies.Nature chemical biology · 2026Review
- Dual RAF inhibition outperforms RAF-MEK combinations for suppressing ERK signaling in KRAS mutant cells.NPJ systems biology and applications · 2026Article
- An effective tumor-inhibiting siRNA delivery platform.Biochemical and biophysical research communications · 2026Article
- Response to a novel type II RAF inhibitor in diffuse leptomeningeal glioneuronal tumor with BRAF fusion.The oncologist · 2025Article
- Exploring the pathway: clinical utility and open challenges of targeting BRAF alterations in biliary tract cancers and gastrointestinal malignancies.ESMO gastrointestinal oncology · 2025Review
- Functional proteoform group deconvolution reveals a broader spectrum of ibrutinib off-targets.Nature communications · 2025Article
- Article
- The paradoxical activity of BRAF inhibitors: potential use in wound healing.Archives of dermatological research · 2025Review
- Prediction and Validation of Novel BRAF Inhibitor as a Potential Drug Candidate for the Treatment of Colorectal Cancer.Current topics in medicinal chemistry · 2025Article
- Multi-output prediction of dose-response curves enables drug repositioning and biomarker discovery.NPJ precision oncology · 2024Article
- The mTOR pathway controls phosphorylation of BRAF at T401.Cell communication and signaling : CCS · 2024Article
- Article
- Computational modeling of drug response identifies mutant-specific constraints for dosing panRAF and MEK inhibitors in melanoma.bioRxiv : the preprint server for biology · 2024Article
- A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.Advances in therapy · 2024Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The RAS-regulated RAF-MEK1/2-ERK1/2 pathway promotes cell proliferation and survival and RAS and BRAF proteins are commonly mutated in cancer. This has fuelled the development of small molecule kinase inhibitors including ATP-competitive RAF inhibitors. Type I and type I½ ATP-competitive RAF inhibitors are effective in BRAFV600E/K-mutant cancer cells. However, in RAS-mutant cells these compounds instead promote RAS-dependent dimerisation and paradoxical activation of wild-type RAF proteins. RAF dimerisation is mediated by two key regions within each RAF protein; the RKTR motif of the αC-helix and the NtA-region of the dimer partner. Dimer formation requires the adoption of a closed, active kinase conformation which can be induced by RAS-dependent activation of RAF or by the binding of type I and I½ RAF inhibitors. Binding of type I or I½ RAF inhibitors to one dimer partner reduces the binding affinity of the other, thereby leaving a single dimer partner uninhibited and able to activate MEK. To overcome this paradox two classes of drug are currently under development; type II pan-RAF inhibitors that induce RAF dimer formation but bind both dimer partners thus allowing effective inhibition of both wild-type RAF dimer partners and monomeric active class I mutant RAF, and the recently developed "paradox breakers" which interrupt BRAF dimerisation through disruption of the αC-helix. Here we review the regulation of RAF proteins, including RAF dimers, and the progress towards effective targeting of the wild-type RAF proteins.
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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.