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A potent new-scaffold androgen receptor antagonist discovered on the basis of a MIEC-SVM model

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Prostate cancer (PCa) is the second most prevalent malignancy among men worldwide. The aberrant activation of androgen receptor (AR) signaling has been recognized as a crucial oncogenic driver for PCa and AR antagonists are widely used in PCa therapy. To develop novel AR antagonist, a machine-learning MIEC-SVM model was established for the virtual screening and 51 candidates were selected and submitted for bioactivity evaluation. To our surprise, a new-scaffold AR antagonist C2 with comparable bioactivity with Enz was identified at the initial round of screening. C2 showed pronounced inhibition on the transcriptional function (IC50 = 0.63 μM) and nuclear translocation of AR and significant antiproliferative and antimetastatic activity on PCa cell line of LNCaP. In addition, C2 exhibited a stronger ability to block the cell cycle of LNCaP than Enz at lower dose and superior AR specificity. Our study highlights the success of MIEC-SVM in discovering AR antagonists, and compound C2 presents a promising new scaffold for the development of AR-targeted therapeutics.

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Fig. 1
Fig. 2
Fig. 3: Performance of the best-performed MIEC model.
Fig. 4: Predicted binding mechanism.
Fig. 5: The effects of C2 on AR signaling.
Fig. 6: C2 attenuated the cell cycle progression of LNCaP cells.
Fig. 7: The cytotoxicity of C2 on PCa cell lines.
Fig. 8: C2 inhibited the migration of LNCaP cells.
Fig. 9: Selectivity of C2 to nuclear receptors MR, GR and PR.

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Acknowledgements

This research was supported by Zhejiang Provincial Natural Science Foundation of China (LD22H300001, 2023C03110) and the National Natural Science Foundation of China (U21A20301).

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Authors and Affiliations

  1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Xin-yue Wang, Xin Chai, Ting-jun Hou & Dan Li

  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, 310022, China

    Lu-hu Shan & Xiao-hong Xu

  3. Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, China

    Lei Xu

  4. State Key Lab of CAD&CG, Zhejiang University, Hangzhou, 310058, China

    Ting-jun Hou

  5. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China

    Hui-yong Sun

  6. Jinhua Institute of Zhejiang University, Jinhua, 321000, China

    Dan Li

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Contributions

DL, TJH, and HYS initiated and supervised the research. XYW, XC, and HYS conducted virtual screening, compound validations and biological assays. LHS, XHX, and LX performed part of in vitro experiments and interpreted part of the data. XYW, XC, HYS, and DL wrote the manuscript, and other authors contributed specific parts of the manuscript. HYS and DL assume responsibility for the manuscript in its entirety. All authors have given approval to the final version of the manuscript.

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Correspondence to Hui-yong Sun or Dan Li.

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Wang, Xy., Chai, X., Shan, Lh. et al. A potent new-scaffold androgen receptor antagonist discovered on the basis of a MIEC-SVM model. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01284-x

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