A potent new-scaffold androgen receptor antagonist discovered on the basis of a MIEC-SVM model.
Acta Pharmacol Sin
; 45(9): 1978-1991, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-38750073
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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Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Próstata
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Receptores Androgénicos
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Proliferación Celular
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Antagonistas de Receptores Androgénicos
Idioma:
En
Revista:
Acta Pharmacol Sin
Asunto de la revista:
FARMACOLOGIA
Año:
2024
Tipo del documento:
Article