Development of Allosteric BRAF Peptide Inhibitors Targeting the Dimer Interface of BRAF
| Autor: | Zhihong Wang, Amber Gunderwala, Anushri A. Nimbvikar, Zhijun Li, Nicholas Cope |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Models Molecular Proto-Oncogene Proteins B-raf endocrine system diseases MAP Kinase Signaling System Allosteric regulation Antineoplastic Agents Protein degradation 01 natural sciences Biochemistry Article 03 medical and health sciences Cell Line Tumor Neoplasms Humans Kinase activity Protein kinase A skin and connective tissue diseases neoplasms Protein Kinase Inhibitors 010405 organic chemistry Chemistry Kinase General Medicine digestive system diseases 0104 chemical sciences enzymes and coenzymes (carbohydrates) 030104 developmental biology Protein kinase domain Cancer cell Cancer research Molecular Medicine Protein Multimerization Peptides |
| Zdroj: | ACS chemical biology. 14(7) |
| ISSN: | 1554-8937 |
| Popis: | BRAF is the most frequently mutated kinase in human cancers and is one of the major effectors of oncogenic RAS, making BRAF a target of considerable interest for anti-cancer drug development. Wild-type BRAF and a variety of oncogenic BRAF mutants are dependent on dimerization of the kinase domain, which also emerges as a culprit of drug resistance and side effects of current BRAF therapies. Thus, allosteric BRAF inhibitors capable of disrupting BRAF dimers could abrogate hyperactivated MAPK (mitogen-activated protein kinase) signaling driven by oncogenic BRAF or RAS and overcome the major limitations of current BRAF inhibitors. To establish this, we applied an in silico approach to design a series of peptide inhibitors targeting the dimer interface of BRAF. One resulting inhibitor was found to potently inhibit the kinase activity of BRAF homo- and heterodimers, including oncogenic BRAF(G469A) mutant. Moreover, this inhibitor synergizes with FDA-approved, ATP-competitive BRAF inhibitors against dimeric BRAF, suggesting that allosteric BRAF inhibitors have great potential to extend the application of current BRAF therapies. Additionally, targeting the dimer interface of BRAF kinase leads to protein degradation of both RAF and MEK, uncovering a novel scaffolding function of RAF in protecting large MAPK complexes from protein degradation. In conclusion, we have developed a potent lead peptide inhibitor for targeting the dimer interface of BRAF in cancer cells. The dual function of this peptide inhibitor validates the strategy for developing allosteric BRAF inhibitors that specifically dissociate RAF dimers and destabilize the MAPK signaling complex. |
| Databáze: | OpenAIRE |
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