Definition

An orally bioavailable heterobifunctional protein degrader of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutant V600E, with potential antineoplastic activity. CFT1946 is comprised of a cereblon (CRBN)-binding moiety and a BRAF V600E-binding moiety. Upon oral administration, BRAF V600E degrader CFT1946 targets and binds to BRAF V600E with its BRAF V600E-binding moiety. Upon BRAF V600E binding, the CRBN-binding moiety binds to CRBN, a component of the CRL4-CRBN E3 ubiquitin ligase complex, which directs proteins for destruction, resulting in the proteasome-mediated degradation of BRAF V600E. This leads to the inhibition of an over-activated MAPK signaling pathway downstream in BRAF V600E-expressing tumor cells and a reduction in tumor cell proliferation. BRAF belongs to the raf/mil family of serine/threonine protein kinases and plays a role in regulating the MAP kinase/ERKs signaling pathway. The valine to glutamic acid substitution at residue 600 accounts for the majority of BRAF gene mutations. The oncogenic product, BRAF V600E, exhibits a markedly elevated activity that over-activates the MAPK signaling pathway.