Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer

The androgen/androgen receptor (AR) signaling pathwayplays animportant role in castration-resistant prostate cancer (CRPC). Bifunctionalagents that simultaneously degrade AR and inhibit androgen synthesisare expected to block the androgen/AR signaling pathway more thoroughly,demonstrating the promising therapeutic potential for CRPC, even enzalutamide-resistantCRPC. Herein, a series of steroid analogs were designed, synthesized,and identified as selective AR degraders, among which YXG-158 (23-h) was the most potent antitumor compound with dual functionsof AR degradation and CYP17A1 inhibition. In addition, 23-h abrogated the hERG inhibition and exhibited excellent PK profiles.In vivo, 23-h effectively inhibited the growth of hormone-sensitiveorgans in the Hershberger assay and exhibited robust antitumor efficacyboth in enzalutamide-sensitive (LNCaP/AR) and enzalutamide-resistant(C4-2b-ENZ) xenograft models. Thus, 23-h was chosen asa preclinical candidate for the treatment of enzalutamide-resistantprostate cancer.

Automated summary

This study designed, synthesized, and identified a series of steroid analogs, among which YXG-158 (23-h) was a selective androgen receptor degrader with dual functions of AR degradation and CYP17A1 inhibition, showing promising therapeutic potential for enzalutamide-resistant prostate cancer.