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

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

  • Bioorg Chem. 2024 Jul:148:107433. doi: 10.1016/j.bioorg.2024.107433.
Wenqiang Zhang 1,  Yawen Fan 1,  Yan Zhang 2,  Yunrui Feng 1,  Yi Luo 1,  Xiaoyu Zhou 1,  Zhuolin Chen 1,  Chenxiao Wang 1,  Tao Lu 3,  Feng Tang 4,  Yadong Chen 5,  Hongmei Li 6,  Yu Jiao 7
Affiliations

Affiliations

  • 1 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China.
  • 2 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China; State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd, 699-18 Xuan Wu Avenue, Nanjing 210042, PR China; Jiangsu Simcere Pharmaceutical Co, Ltd, 699-18 Xuan Wu Avenue, Nanjing 210042, PR China.
  • 3 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 4 State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd, 699-18 Xuan Wu Avenue, Nanjing 210042, PR China; Jiangsu Simcere Pharmaceutical Co, Ltd, 699-18 Xuan Wu Avenue, Nanjing 210042, PR China. Electronic address: feng.tang@cn.simcere.com.
  • 5 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China. Electronic address: ydchen@cpu.edu.cn.
  • 6 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China. Electronic address: liashry@163.com.
  • 7 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China. Electronic address: jiaoyu@cpu.edu.cn.
PMID: 38754311 DOI: 10.1016/j.bioorg.2024.107433
Abstract

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.

Keywords

Androgen receptor; Biphenyl derivatives; Degraders; Prostate cancer.

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