Mechanism and inhibition of BRAF kinase |
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| Institution: | 1. Department of Pharmacology, University of California San Diego, USA;2. Department of Chemistry and Biochemistry, University of California Los Angeles, USA;3. Department of Bioengineering, University of California San Diego, USA;4. Department of Chemistry and Biochemistry, University of California San Diego, USA;1. Department of Chemistry, University of California, Berkeley, CA, 94720, USA;2. Department of Molecular & Cell Biology, University of California, Berkeley, CA, 94720, USA;3. Helen Wills Neuroscience Institute, University of California, Berkeley, CA, 94720, USA;1. Department of Chemistry, Wayne State University, Detroit, MI 48202, USA;2. Department of Chemistry, Drexel University, Philadelphia, PA 19104, USA;1. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, CB10 1SD, UK;2. Open Targets, Wellcome Genome Campus, Cambridge, CB10 1SA, UK;3. Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, 8093, Switzerland |
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| Abstract: | The role of BRAF in tumor initiation has been established, however, the precise mechanism of autoinhibition has only been illustrated recently by several structural studies. These structures uncovered the basis by which the regulatory domains engage in regulating the activity of BRAF kinase domain, which lead to a more complete picture of the regulation cycle of RAF kinases. Small molecule BRAF inhibitors developed specifically to target BRAFV600E have proven effective at inhibiting the most dominant BRAF mutant in melanomas, but are less potent against other BRAF mutants in RAS-driven diseases due to paradoxical activation of the MAPK pathway. A variety of new generation inhibitors that do not show paradoxical activation have been developed. Alternatively, efforts have begun to develop inhibitors targeting the dimer interface of BRAF. A deeper understanding of BRAF regulation together with more diverse BRAF inhibitors will be beneficial for drug development in RAF or RASdriven cancers. |
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| Keywords: | RAS RAF kinase Autoinhibition 14-3-3 RAS-RAF interaction Paradoxical activation Allosteric kinase inhibitor |
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