Proteolysis-targeting chimera (PROTAC)-mediated protein degradation is a rapidly emerging therapeutic intervention that induces the degradation of targeted proteins. Herein, we report the design and biological evaluation of a series of androgen receptor (AR) PROTAC degraders for the treatment of metastatic castration-resistant prostate cancer. Predominantly, instead of thalidomide, we utilized the TD-106 scaffold, a novel cereblon (CRBN) binder that was identified in our previous study. Our results suggest that the linker position in the TD-106 CRBN binder is critical for the efficiency of AR degradation. The compounds attached to the 6-position of TD-106 promoted better degradation of AR than those at the 5- and 7-positions. Among the synthesized AR PROTACs, the representative degrader 33c (TD-802) effectively induced AR protein degradation, with a degradation concentration 50% of 12.5 nM and a maximum degradation of 93% in LNCaP prostate cancer cells. Additionally, most AR PROTAC degraders, including TD-802, displayed good liver microsomal stability and in vivo pharmacokinetic properties. Finally, we showed that TD-802 effectively inhibited tumor growth in an in vivo xenograft study.

靶向蛋白水解的嵌合体（PROTAC）介导的蛋白质降解是一种迅速出现的治疗性干预措施，可诱导目标蛋白质的降解。在此，我们报告了一系列雄激素受体（AR）PROTAC降解剂的设计和生物学评估，该降解剂用于治疗转移性去势抵抗性前列腺癌。我们主要使用TD-106支架代替沙利度胺，TD-106支架是在我们先前的研究中鉴定出的新型大脑（CRBN）粘合剂。我们的结果表明，TD-106 CRBN粘合剂中的接头位置对AR降解效率至关重要。与在TD-106的6位上连接的化合物比在5和7位上的化合物促进了更好的AR降解。在合成的AR PROTAC中，代表性的降解物33c（TD-802）有效诱导AR蛋白降解，在LNCaP前列腺癌细胞中降解浓度为12.5 nM，50％，最大降解为93％。此外，大多数AR PROTAC降解物，包括TD-802，都具有良好的肝微粒体稳定性和体内药代动力学特性。最后，我们在体内异种移植研究中显示TD-802有效抑制肿瘤生长。