Design, synthesis, and biological evaluation of small molecule PROTACs for potential anticancer effects

Androgen receptor (AR) reactivation was closely related with the recurrence of human prostate cancer. Currently, several limitations of AR inhibitors impede their application, such as the acquired drug resistance and the potential off-target binding. Recently, proteolysis targeting chimera (PROTAC) has been used to treat various diseases by degrading target proteins, which has shown higher selectivity than the corresponding inhibitor. In this study, PAP508 was developed as a novel PROTAC degrader of AR proteins. The results suggested the effect of PAP508 on AR protein depended on the action of proteasome, furthermore, the degradation effect was concentration- and time-dependent manner in LNCaP and VCaP cells. PAP508 can inhibit the proliferation, migration, and invasion of prostate cancer cells. These data suggested that PAP508 is a potent and efficacious compound for the development of PROTAC targeted AR.