Evaluationof Cereblon-Directing Warheads for theDevelopment of Orally Bioavailable PROTACs

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall <i>in vitro</i> degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor <i>in vivo</i> pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (<b>8</b>), and results of a comprehensive <i>in vitro/vivo</i> comparative study with analogues containing alternative CRBN-directing warheads. Our study highlights the importance of considering warhead modifications when optimizing PROTACs for oral delivery.