Development of Allosteric BRAF Peptide Inhibitors Targeting the Dimer Interface of BRAF

Amber Y. Gunderwala, Anushri A. Nimbvikar, Nicholas J. Cope, Zhijun Li, Zhihong Wang

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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 anticancer 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 BRAFG469A 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.

Original languageEnglish (US)
Pages (from-to)1471-1480
Number of pages10
JournalACS Chemical Biology
Volume14
Issue number7
DOIs
StatePublished - Jun 3 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

Fingerprint

Dive into the research topics of 'Development of Allosteric BRAF Peptide Inhibitors Targeting the Dimer Interface of BRAF'. Together they form a unique fingerprint.

Cite this