Design, Synthesis, and Biological Evaluation of Androgen Receptor Degrading and Antagonizing Bifunctional Steroidal Analogs for the Treatment of Advanced Prostate Cancer

Metastatic castration-resistant prostate cancer (mCRPC)
with high
mortality has seriously threatened men’s health. Bifunctional
agents simultaneously degrade and antagonize androgen receptor (AR),
display robust AR signaling pathway blockade, and show the therapeutic
prospect for mCRPC. Herein, systemic structural modifications on the
C-3, C-6, and C-17 positions of galeterone led to the discovery of 67-b with the dual functions of AR antagonism and degradation. In vitro, 67-b exhibited excellent antiproliferative
activity and potent AR degradation activity in different PCa cells
(LNCaP and 22RV1), as well as outstanding antagonistic activity against
wild-type and mutant (W741L, T877A, and F876L) ARs. In vivo, 67-b effectively inhibited the growth of hormone-sensitive
organs in the Hershberger assay and exhibited tumor regression in
the enzalutamide-resistant (c4-2b–ENZ) xenograft model. These
results confirmed 67-b to be a promising AR degrader
and antagonist for the treatment of mCRPC patients.