2. Academic Validation
  3. A novel small-molecule androgen receptor antagonist selective for the T878A-mutant AR in prostate cancer therapy

A novel small-molecule androgen receptor antagonist selective for the T878A-mutant AR in prostate cancer therapy

  • Eur J Med Chem. 2026 Aug 5:312:118862. doi: 10.1016/j.ejmech.2026.118862.
Yangyang Zheng 1,  Xin Chai 1,  Huating Wang 1,  Zihan Yan 1,  Zhaoyang Lin 1,  Luhu Shan 2,  Xinyue Wang 1,  Ganpeng Du 1,  Qunce Ren 3,  Xiaohong Xu 2,  Wenteng Chen 1,  Tingjun Hou 4,  Dan Li 5
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 2 Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, China.
  • 3 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Zhejiang Key Laboratory of Intelligent Drug Discovery and Development & Zhejiang Provincial Engineering Research Center for Innovative Small-Molecule Drugs, Jinhua Institute of Zhejiang University, Jinhua, Zhejiang, 321000, China.
  • 4 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Zhejiang Key Laboratory of Intelligent Drug Discovery and Development & Zhejiang Provincial Engineering Research Center for Innovative Small-Molecule Drugs, Jinhua Institute of Zhejiang University, Jinhua, Zhejiang, 321000, China. Electronic address: [email protected].
  • 5 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China; Zhejiang Key Laboratory of Intelligent Drug Discovery and Development & Zhejiang Provincial Engineering Research Center for Innovative Small-Molecule Drugs, Jinhua Institute of Zhejiang University, Jinhua, Zhejiang, 321000, China. Electronic address: [email protected].
PMID: 42030710 DOI: 10.1016/j.ejmech.2026.118862
Abstract

Prostate Cancer (PCa) is one of the most prevalent malignancies in males. While Androgen Receptor (AR) antagonists play a crucial role in PCa therapy, their efficacy is often limited by resistance arising from AR mutations. Here, we identified S-94, corresponding to the S-enantiomer of compound 94, as a novel AR antagonist with marked selectivity for the T878A-mutant AR. In vitro, S-94 inhibited AR transcriptional activity (IC50 = 0.38 μM) and suppressed cell proliferation (IC50 = 10.32 μM) in LNCaP cells harboring the T878A-mutant AR, while exhibiting lower cytotoxicity toward non-cancerous cells. In vivo, S-94 (20 mg/kg, i.p.) inhibited tumor growth in an LNCaP xenograft model. Mechanistic studies showed that S-94 selectively targeted the T878A-mutant AR, exhibiting 50-fold greater potency against ART878A (IC50 = 0.49 μM) than against wild-type AR (IC50 = 27.18 μM). Moreover, S-94 antagonized several clinically relevant T878A-associated AR mutants, including ARF877L/T878A and ARH875Y/T878A, and displayed high selectivity over GR, MR, and PR. In summary, the study suggests that S-94 targets the T878A-mutant AR as a selective AR antagonist with limited impact on the physiological wild-type AR, and effectively antagonizes clinically relevant T878A-associated AR mutants. These properties highlight S-94 as a promising and potentially safer lead compound for the treatment of prostate cancers harboring T878A-associated AR mutations.

Keywords

Androgen receptor antagonist; Drug resistance; Prostate cancer; T878A mutation; Targeted therapy.

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