Rapidly Accelerated Fibrosarcoma kinase dimers (RAF kinase dimers)

Rapidly Accelerated Fibrosarcoma (RAF) kinase dimers, consisting of ARAF, BRAF, and CRAF isoforms, are essential regulatory complexes within the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. Dimerization is a physiological requirement for the activation of RAF kinases, typically triggered by the binding of active RAS proteins to the RAF regulatory domain. In many cancers, mutations in RAS or specific non-V600 BRAF mutations promote constitutive RAF dimerization, leading to uncontrolled cell proliferation and survival. While first-generation BRAF inhibitors effectively target V600E monomers, they often paradoxically induce dimerization and pathway activation in RAS-mutant contexts, a phenomenon known as paradoxical activation. Consequently, next-generation 'dimer-breaker' or pan-RAF inhibitors are being developed to target the dimeric state directly or inhibit both protomers within the dimer to overcome resistance and improve therapeutic outcomes in RAS-driven and RAF-mutant malignancies.

Other names

RAF-RAF dimersBRAF-CRAF heterodimersBRAF homodimersCRAF homodimersARAF-CRAF heterodimersDimerized RAF kinases

ATP-competitive inhibition of the kinase domain within the dimeric complex, prevention of RAF dimerization, or pan-RAF inhibition targeting both monomeric and dimeric forms to prevent paradoxical MAPK pathway activation.