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  3. Discovery of novel indole derivatives as LRH-1 antagonists for the treatment of castration resistant prostate cancer

Discovery of novel indole derivatives as LRH-1 antagonists for the treatment of castration resistant prostate cancer

  • Eur J Med Chem. 2026 Apr 15:308:118681. doi: 10.1016/j.ejmech.2026.118681.
Kaiyuan Ma 1,  Weiqin Jin 2,  Yan Zhang 3,  Zhifang Lu 4,  Xiaoxi Zhuang 3,  Junhua Li 3,  Xinyi Jing 2,  Jun Wang 4,  Liang Li 5,  Yanan Zhou 5,  Xin Li 5,  Tingting Xu 3,  Jinxin Xu 3,  Jinming Ma 6,  Junjie Deng 7,  Xin Zhai 8,  Bin Lin 9,  Yong Xu 10,  Hui Shen 11
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 Institute of Health Sciences and Technology, Institutes of Physical Science and Information Technology, Anhui University, Hefei, 230601, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 3 China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 5 Qilu Pharmaceutical Co., Ltd, Jinan, 250101, China.
  • 6 Institute of Health Sciences and Technology, Institutes of Physical Science and Information Technology, Anhui University, Hefei, 230601, China.
  • 7 Qilu Pharmaceutical Co., Ltd, Jinan, 250101, China. Electronic address: junjie.deng@qilu-pharma.com.
  • 8 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: zhaixin_syphu@126.com.
  • 9 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: randybinlin@sina.com.
  • 10 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. Electronic address: xu_yong@gibh.ac.cn.
  • 11 China-New Zealand Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. Electronic address: shen_hui17@gibh.ac.cn.
PMID: 41719800 DOI: 10.1016/j.ejmech.2026.118681
Abstract

Liver receptor homolog-1 (LRH-1) is a key regulator in multiple cancers, including prostate Cancer, making its antagonists a promising therapeutic strategy. However, the development of potent LRH-1 antagonists remains largely inadequate, underscoring an urgent unmet need for novel candidates with therapeutic potential. Herein, we report the discovery and characterization of a novel class of indole-based LRH-1 antagonists. Starting from high-throughput virtual screening, we employed structure-based drug design strategy to optimize lead compounds, yielding 26 (XY25026) and 28 (XY25028), which exhibit potent LRH-1inhibition with IC50 values of 280 nM and 300 nM, respectively. In cellular assays, 26 and 28 inhibited the cell proliferation across a panel of Androgen Receptor (AR)-positive prostate Cancer cell lines with distinct androgen responsiveness and AR signaling profiles and suppressed AR target genes (KLK2 and KLK3). Importantly, oral administration of 26 and 28 elicited significant in vivo antitumor efficacy in a 22Rv1 xenograft model, with no detectable systemic toxicity observed in treated mice. These results identify 26 and 28 as promising orally bioavailable LRH-1 antagonists, validating them as attractive lead molecules for further structural optimization and development for castration-resistant prostate Cancer (CRPC) therapy.

Keywords

Antagonist; Castration-resistant prostate cancer; LRH-1; Nuclear receptor.

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