2. Academic Validation
  3. Discovery of thiohydantoin based antagonists of androgen receptor with efficient degradation for the treatment of prostate cancer

Discovery of thiohydantoin based antagonists of androgen receptor with efficient degradation for the treatment of prostate cancer

  • Eur J Med Chem. 2023 Sep 5;257:115490. doi: 10.1016/j.ejmech.2023.115490.
Xiujin Chang 1,  Di Zhang 1,  Fangui Qu 1,  Youquan Xie 1,  Tian Chen 1,  Yuqing Zhang 1,  Qianming Du 2,  Jinlei Bian 1,  Zhiyu Li 1,  Jubo Wang 3,  Xi Xu 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 2 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: 1620194588@cpu.edu.cn.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: xuxi@cpu.edu.cn.
PMID: 37209451 DOI: 10.1016/j.ejmech.2023.115490
Abstract

Prostate Cancer (PC) is one of the most prevalent cancers in men worldwide, and Androgen Receptor (AR) is a well-validated drug target for the treatment of PC. However, PC often exhibits resistance to AR antagonists over time. Thus, it is urgent to identify novel and effective drugs for PC treatment. A series of novel thiohydantoin based AR antagonists with efficient degradation against AR were designed, synthesized, and evaluated. Based on our previous SAR and further structural optimization, a tool molecule 26h was discovered with dual mechanisms including improved antagonistic activity and potent degradation (AR-fl and AR-V7). Moreover, 26h can also effectively block AR nuclear translocation and inhibit AR/AR-V7 heterodimerization, thereby inhibiting downstream gene transcription. Importantly, 26h displayed potent robust efficacy in LNCaP (TGI: 70.70%) and 22Rv1 (TGI: 78.89%) xenograft models. This provides new design strategies and advantageous potential compounds for the treatment of prostate Cancer.

Keywords

Androgen receptor; Antagonist; Degradation; Prostate cancer.

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