B-Raf kinase (BRAF)

B-Raf kinase is a member of the RAF family of serine/threonine-protein kinases and plays a central role in the RAS-RAF-MEK-ERK signaling cascade, which transmits mitogenic signals from the cell surface to the nucleus to control cell proliferation and survival[3][8]. BRAF forms functional dimers—either as homo- (BRAF-BRAF) or heterodimers (often with CRAF)—following activation by upstream RAS signaling. Dimerization is required for normal RAF function and is also a key factor in drug sensitivity and resistance. In cancers, BRAF mutations (most commonly V600E) frequently alter the dimerization requirement: class I mutations (like V600E) usually signal as monomers, while class II/III mutations promote constitutive dimerization and are associated with resistance to first-generation BRAF inhibitors[8]. Many kinase inhibitors directly target the ATP-binding site and may promote either inhibition or paradoxical activation depending on dimer context, leading to therapeutic challenges and toxicity[4][5][8]. Second-generation BRAF inhibitors aim to more comprehensively inhibit both monomeric and dimeric forms for improved efficacy and reduced paradoxical effects[1][2][8].

Other names

BRAFB-RafSerine/threonine-protein kinase B-rafv-raf murine sarcoma viral oncogene homolog B1

Inhibition of kinase activity (ATP-competitive inhibition) Disruption of dimerization (dimer-selective inhibitors) Paradoxical activation/transactivation of wild-type dimers by certain inhibitors