Direct-to-Biology Discovery of Potent FBXO22 Homo-PROTACs
- We used a direct-to-biology approach to rapidly interrogate FBXO22-mediated degradation of 4 distinct targets (BRD4, BTK, CRBN and VHL), as well as the degradation of FBXO22 itself by 3 different E3 ligases
- Parallel synthesis of 175 candidate PROTACs containing primary alkylamine FBXO22 warheads, followed by direct testing of crude reaction products in cellular HiBiT assays, accelerated the discovery of highly potent and novel FBXO22 homo-PROTACs that induce self-degradation, as well as CRBN- and VHL-mediated degraders of FBXO22
- We show that FBXO22 homo-PROTACs induce ternary complex formation and the degradation in a proteasome dependent manner, supporting the selfdegradation mechanism