Designed, synthesized and biological evaluation of proteolysis targeting chimeras (PROTACs) as AR degraders for prostate cancer treatment

As a continuation of our research on developing potent and potentially safe androgen receptor (AR) degrader, a series of novel proteolysis targeting chimeras (PROTACs) containing the phthalimide degrons with different linker were designed, synthesized and evaluated for their AR degradation activity against LNCaP (AR+) cell line. Most of the synthesized compounds displayed moderate to satisfactory AR binding affinity and might lead to antagonist activity against AR. Among them, compound A16 exhibited the best AR binding affinity (85%) and degradation activity against AR. Due to the strong fluorescence properties of pomalidomide derivatives, B10 was found to be effectively internalized and visualized in LNCaP (AR + ) cells than PC-3 (AR-) cells. Moreover, the molecular docking of A16 with AR and the active site of DDB1-CRBN E3 ubiquitin ligase complex provides guidance to design new PROTAC degrons targeting AR for prostate cancer therapy. These results represent a step toward the development of novel and improved AR PROTACs.

Automated summary

In this study, novel PROTACs containing different linker phthalimide degrons were designed, synthesized, and evaluated for their AR degradation activity. Compound A16 showed the best AR binding affinity and degradation activity, while B10 exhibited effective internalization and visualization in LNCaP cells. Molecular docking of A16 with AR and the DDB1-CRBN E3 ubiquitin ligase complex provides guidance for designing new PROTAC degrons targeting AR in prostate cancer therapy. This research represents progress towards developing novel and improved AR PROTACs.