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J Med Chem. 2014 Aug 14;57(15):6458-67. doi: 10.1021/jm500802j. Epub 2014 Aug 4.

Discovery of small-molecule inhibitors selectively targeting the DNA-binding domain of the human androgen receptor.

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Vancouver Prostate Centre, University of British Columbia , 2660 Oak Street, Vancouver, British Columbia V6H 3Z6, Canada.


The human androgen receptor (AR) is considered as a master regulator in the development and progression of prostate cancer (PCa). As resistance to clinically used anti-AR drugs remains a major challenge for the treatment of advanced PCa, there is a pressing need for new anti-AR therapeutic avenues. In this study, we identified a binding site on the DNA binding domain (DBD) of the receptor and utilized virtual screening to discover a set of micromolar hits for the target. Through further exploration of the most potent hit (1), a structural analogue (6) was identified demonstrating 10-fold improved anti-AR potency. Further optimization resulted in a more potent synthetic analogue (25) with anti-AR potency comparable to a newly FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated that the developed inhibitors do interact with the intended target site. Importantly, the AR DBD inhibitors could effectively inhibit the growth of Enzalutamide-resistant cells as well as block the transcriptional activity of constitutively active AR splice variants, such as V7.

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