Targeting the Protein-Protein Interaction Between the CDC37 Co-Chaperone and Client Kinases by an Allosteric RAF Dimer Breaker.

Braftide, originally designed as a potent allosteric RAF kinase dimer disruptor, was intended to inhibit RAF dimerization by targeting the conserved RAF dimer interface. Intriguingly, Braftide has also been observed to trigger proteasome-mediated protein degradation with an unclear mechanism of action. This study elucidates the mechanism underlying Braftide's dual functionality and assesses its potential as a chemical probe to target kinase-chaperone interaction.

Unveiling the domain-specific and RAS isoform-specific details of BRAF kinase regulation.

BRAF is a key member in the MAPK signaling pathway essential for cell growth, proliferation, and differentiation. Mutant BRAF is often the underlying cause of various types of cancer and mutant RAS, the upstream regulator of BRAF, is a driver of up to one-third of all cancers. BRAF interacts with RAS and undergoes a conformational change from an inactive, autoinhibited monomer to an active dimer, which propagates downstream signaling.

Unveiling the Domain-Specific and RAS Isoform-Specific Details of BRAF Regulation.

BRAF is a key member in the MAPK signaling pathway essential for cell growth, proliferation, and differentiation. Dysregulation or mutation of BRAF is often the underlying cause of various types of cancer. RAS, a small GTPase protein that acts upstream of BRAF, has been identified as a driver of up to one-third of all cancers.