2. Academic Validation
  3. Discovery of novel tetrahydroquinoline derivatives as potent, selective, and orally Available AR antagonists

Discovery of novel tetrahydroquinoline derivatives as potent, selective, and orally Available AR antagonists

  • Eur J Med Chem. 2025 Jul 5:291:117566. doi: 10.1016/j.ejmech.2025.117566.
Leer Yuan 1,  Jianing Liao 1,  Yiyang Qin 1,  Lvtao Cai 2,  Minkui Zhang 1,  Jinbiao Liao 1,  Dan Li 3,  Tingjun Hou 2,  Rong Sheng 4
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Jinhua Institute of Zhejiang University, Zhejiang University, Jinhua, 321036, China.
  • 3 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Jinhua Institute of Zhejiang University, Zhejiang University, Jinhua, 321036, China. Electronic address: lidancps@zju.edu.cn.
  • 4 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Jinhua Institute of Zhejiang University, Zhejiang University, Jinhua, 321036, China. Electronic address: shengr@zju.edu.cn.
PMID: 40188583 DOI: 10.1016/j.ejmech.2025.117566
Abstract

Androgen Receptor (AR) antagonists are the first-line medicine for the treatment of prostate Cancer (PCa) in clinic. In our previous work, the tetrahydroquinoline derivative AT2 was identified as a novel scaffold AR antagonist via virtual screening and structural modifications, while its poor pharmacokinetic properties hindered further development. Herein, we report the systematic structural optimizations of AT2 and discover a novel tetrahydroquinoline derivative C2 as potent AR antagonist with an IC50 value of 0.019 μM, accompanied with excellent selectivity over Other nuclear receptors (PR, GR, MR). Further biological assays revealed that C2 significantly inhibited LNCaP cell proliferation, and efficiently reduced PSA protein expression. Especially, C2 showed superior efficacy against ARF877L/T878A mutants compared to darolutamide and enzalutamide. Furthermore, C2 demonstrated excellent oral bioavailability, indicating the potential to enhance in vivo efficacy and to serve as a promising therapeutic option for PCa treatment.

Keywords

Androgen receptor antagonist; Molecular docking; Prostate cancer; Structure-activity relationship.

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