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Novel androgen receptor antagonist identified by structure-based virtual screening, structural optimization, and biological evaluation.

Abstract：

:Androgen receptor (AR) plays important roles in the development of prostate cancer (PCa), and therefore it has been regarded as the most important therapeutic target for both hormone-sensitive prostate cancer (HSPC) and advanced PCa. In this study, a novel hit (C18) with IC50 of 2.4 μM against AR transcriptional activity in LNCaP cell was identified through structure-based virtual screening based on molecular docking and free energy calculations. The structure-activity relationship analysis and structural optimization of C18 resulted in the discovery of a structural analogue (AT2), a more potent AR antagonist with 16-fold improved anti-AR potency. Further assays indicated that AT2 was capable of effectively inhibiting the transcriptional function of AR and blocking the nuclear translocation of AR like the second-generation AR antagonists. The antagonists discovered in this study may be served as the promising lead compounds for the development of AR-driven PCa therapeutics.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Tang Q,Fu W,Zhang M,Wang E,Shan L,Chai X,Pang J,Wang X,Xu X,Xu L,Li D,Sheng R,Hou T

doi

10.1016/j.ejmech.2020.112156

subject

Has Abstract

pub_date

2020-04-15 00:00:00

pages

112156

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30123-9

journal_volume

192

pub_type

杂志文章

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