molecules of the month

A protein degradation approach to overcome paradoxical RAF activation. CFT1946 from C4 Therapeutics is a potent, selective, and orally bioavailable bifunctional degrader of mutant BRAF in Ph. I/II for the treatment of BRAF-driven solid tumors, alone and in combo with a MEK1/2 inhibitor (trametinib) (NCT05668585). BRAF-V600X is clinically validated with approved drugs (e.g. vemurafenib), but traditional inhibitors face challenges in selectivity over wildtype BRAF and can cause paradoxical RAF activation. Paradoxical RAF activation occurs when BRAF kinase inhibitors promote the formation of signaling RAF dimers through a scaffolding effect by the BRAF-inhibitor complex, activating WT RAF. This paradoxical activation can cause unintended side effects and decreased efficacy in targeted cancer therapies - for example, paradoxical activation of MAPK signaling can…