Evaluation of Cereblon-Directing Warheads for the Development 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 in vitro degradation
and antiproliferative activities compared to its direct thalidomide-based
analogue dBET1, but similarly poor in vivo 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 (8), and results of a comprehensive in
vitro/vivo comparative study with analogues containing alternative
CRBN-directing warheads. Our study highlights the importance of considering
warhead modifications when optimizing PROTACs for oral delivery.