Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer

Meng Wu; Rongyu Zhang; Zixiong Zhang; Ning Zhang; Chenfan Li; Yongli Xie; Haoran Xia; Fangjiao Huang; Ruoying Zhang; Ming Liu; Xiaoyu Li; Shan Cen; Jinming Zhou

doi:10.7554/eLife.70700

eLife (Jan 2023)

Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer

Meng Wu,
Rongyu Zhang,
Zixiong Zhang,
Ning Zhang,
Chenfan Li,
Yongli Xie,
Haoran Xia,
Fangjiao Huang,
Ruoying Zhang,
Ming Liu,
Xiaoyu Li,
Shan Cen,
Jinming Zhou

Affiliations

Meng Wu: ORCiD; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China; Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China; Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Rongyu Zhang: ORCiD; Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, China
Zixiong Zhang: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China
Ning Zhang: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China
Chenfan Li: Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, China
Yongli Xie: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China
Haoran Xia: Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
Fangjiao Huang: Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, China
Ruoying Zhang: Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, China
Ming Liu: Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
Xiaoyu Li: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China
Shan Cen: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China
Jinming Zhou: ORCiD; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China; Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua, China

DOI: https://doi.org/10.7554/eLife.70700
Journal volume & issue: Vol. 12

Abstract

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In patients with castration-resistant prostate cancer (CRPC), clinical resistances such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) limit the effectiveness of second-generation antiandrogens (SGAs). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. Here, we found and identified a bifunctional small molecule Z15, which is both an effective AR antagonist and a selective AR degrader. Z15 could directly interact with the ligand-binding domain (LBD) and activation function-1 region of AR, and promote AR degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 efficiently suppressed AR, AR mutants and ARVs transcription activity, downregulated mRNA and protein levels of AR downstream target genes, thereby overcoming AR LBD mutations, AR amplification, and ARVs-induced SGAs resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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