Current Insights of BRAF Inhibitors in Cancer

Research output: Contribution to journalReview article

18 Scopus citations

Abstract

Oncogenic BRAF kinase deregulates the ERK signaling pathway in a large number of human tumors. FDA-approved BRAF inhibitors for BRAFV600E/K tumors have provided impressive clinical responses extending survival of melanoma patients. However, these drugs display paradoxical activation in normal tissue with BRAFWT due to RAF transactivation and priming, acquired drug resistance, and limited clinical effectiveness in non-V600 BRAF-dependent tumors, underscoring the urgent need to develop improved BRAF inhibitors. This review provides an overview of recent structural and biochemical insights into the mechanisms of BRAF regulation by BRAF inhibitors that are linked to their clinical activity, clinical liabilities, and medicinal chemistry properties. The effectiveness and challenges of structurally diverse next generation RAF inhibitors currently in preclinical and clinical development are discussed, along with mechanistic insights for developing more effective RAF inhibitors targeting different oncogenic BRAF conformations.

Original languageEnglish (US)
Pages (from-to)5775-5793
Number of pages19
JournalJournal of Medicinal Chemistry
Volume61
Issue number14
DOIs
StatePublished - Jul 26 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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