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.

蛋白水解靶向嵌合体（PROTACs）通常处于经典类药物分子所定义的理化空间范畴之外，这往往为其口服给药的优化与开发带来显著挑战。我们此前曾报道过基于苯基戊二酰亚胺（phenyl glutarimide, PG）的BET PROTAC SJ995973，相较于其直接基于沙利度胺的同源类似物dBET1，其整体体外降解活性与抗增殖活性更为优异，但体内药代动力学特性同样欠佳。为进一步验证PG的应用价值，本文报道了经优化研究得到的口服生物可利用性BET-PROTAC SJ44236（8），以及与携带不同靶向cereblon（CRBN）弹头的类似物开展的全面体内外比较研究结果。本研究强调了在优化用于口服递送的PROTACs时，考量弹头修饰的重要性。