Mechanism and inhibition of BRAF kinase

Amber Gunderwala, Nicholas Cope, Zhihong Wang

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish (US)
Article number102205
JournalCurrent Opinion in Chemical Biology
Volume71
DOIs
StatePublished - Dec 2022

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Biochemistry

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