2. Academic Validation
  3. Identification of the gossypol derivatives as androgen receptor inhibitor

Identification of the gossypol derivatives as androgen receptor inhibitor

  • Bioorg Med Chem Lett. 2022 Nov 1:75:128952. doi: 10.1016/j.bmcl.2022.128952.
Rongyu Zhang 1,  Meng Wu 2,  Tongxiang Cao 3,  Kui Luo 4,  Fangjiao Huang 1,  Ruoying Zhang 1,  Zhipeng Huang 4,  Jinming Zhou 5,  Yongdong Wang 6,  Shifa Zhu 7
Affiliations

Affiliations

  • 1 Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, PR China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, PR China.
  • 3 Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, PR China.
  • 4 Singfar Laboratories, Guangzhou 510670, PR China.
  • 5 Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, PR China. Electronic address: zhoujinming@zjnu.edu.cn.
  • 6 Singfar Laboratories, Guangzhou 510670, PR China. Electronic address: ydwang@vip.163.com.
  • 7 Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, PR China. Electronic address: zhusf@scut.edu.cn.
PMID: 36031018 DOI: 10.1016/j.bmcl.2022.128952
Abstract

Prostate Cancer (PCa) is the most frequently diagnosed male malignant tumor and remains the second leading cause of male Cancer mortality in western countries. The development of novel antiandrogens to circumvent the drug resistance in anti-PCa treatment is highly demanded. Herein, we identified that gossypol (GOS) specificly inhibited the AR signaling. Further optimization of GOS derivatives led to the discovery of compound XY-32. XY-32 efficiently inhibits AR signaling with the IC50 of 1.23 μM. XY-32 downregulates both the full-length AR and the AR variable splice AR-V7 via suppressing the mRNA expression. It inhibits the proliferation of CRPC cells such as the LNCaP cells, the PC-3 cells, and enzalutamide resistance 22Rv1 cells. The work demonstrates the GOS derivatives represent a novel series of anti-androgen to conquer the acquired AR mutations or AR splice variants induced drug resistance of mCRPC.

Keywords

Androgen receptor; Enzalutamide resistance; Gossypol; Inhibitor; Prostate cancer.

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