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

   
@article{APS11094,
	author = {Xin-yue Wang and Xin Chai and Lu-hu Shan and Xiao-hong Xu and Lei Xu and Ting-jun Hou and Hui-yong Sun and Dan Li},
	title = {A potent new-scaffold androgen receptor antagonist discovered on the basis of a MIEC-SVM model},
	journal = {Acta Pharmacologica Sinica},
	volume = {45},
	number = {9},
	year = {2024},
	keywords = {},
	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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/11094}
}