CFT1946 is an Orally Available Brain-Penetrant BRAFV600-Mutant Degrader that Overcomes BRAF Inhibitor Resistance.

Abstract Currently approved BRAF inhibitors (BRAFi) have achieved impressive efficacy in BRAFV600-mutant cancers. However, clinical benefit of BRAFi is limited by several factors, including vulnerability to RAF-dimer driven resistance mechanisms, poor brain penetration, and side effects arising from paradoxical activation of MAPK signaling in normal tissue. Here, we aimed to overcome these limitations by developing CFT1946, a potent, orally bioavailable, and brain-penetrant cereblon-based bifunctional degrader that targets BRAFV600-mutant protein while sparing wild-type (WT) RAF family members. CFT1946 demonstrated potent activity in preclinical models of BRAFV600-mutant driven melanoma and colorectal cancer (CRC) while sparing WT MAPK signaling and mitigating the paradoxical activation associated with approved BRAFi. CFT1946 was efficacious in an intracranial BRAFV600E melanoma tumor model and demonstrated robust activity in multiple cellular and patient-derived BRAFV600-mutant melanoma and CRC models of acquired and adaptive RAF-dimer driven BRAFi-resistance. CFT1946 therefore represents an effective therapeutic modality with the potential to overcome the key limitations of current BRAFV600-mutant targeted therapies.