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

Authors :
Wang XY
Chai X
Shan LH
Xu XH
Xu L
Hou TJ
Sun HY
Li D
Source :
Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Sep; Vol. 45 (9), pp. 1978-1991. Date of Electronic Publication: 2024 May 15.
Publication Year :
2024

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 (IC <subscript>50</subscript>  = 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.<br /> (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Details

Language :
English
ISSN :
1745-7254
Volume :
45
Issue :
9
Database :
MEDLINE
Journal :
Acta pharmacologica Sinica
Publication Type :
Academic Journal
Accession number :
38750073
Full Text :
https://doi.org/10.1038/s41401-024-01284-x