Discovery of novel biphenyl derivatives as androgen receptor degraders for the treatment of enzalutamide-resistant prostate cancer

[Display omitted] •A series of biphenyl derivatives were identified as bifunctional AR antagonists and degraders.•Compound 14k exhibited superior in vitro antiproliferative activity than UT-155 toward enzalutamide-resistant 22Rv1 cells.•Compound 14k and 7a significantly induced a decrease in AR protein abundance in 22Rv1 cells. Second-generation AR antagonists, such as enzalutamide, are the primary therapeutic agents for advanced prostate cancer. However, the development of both primary and secondary drug resistance leads to treatment failures and patient mortality. Bifunctional agents that simultaneously antagonize and degrade AR block the AR signaling pathway more completely and exhibit excellent antiproliferative activity against wild-type and drug-resistant prostate cancer cells. Here, we reported the discovery and optimization of a series of biphenyl derivatives as androgen receptor antagonists and degraders. These biphenyl derivatives exhibited potent antiproliferative activity against LNCaP and 22Rv1 cells. Our discoveries enrich the diversity of small molecule AR degraders and offer insights for the development of novel AR degraders for the treatment of enzalutamide-resistant prostate cancer.