Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 15, Pages 6458-6467Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm500802j
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Funding
- Prostate Cancer Canada
- Canada Safeway [SP2013-02, 272111]
- Canadian Institutes of Health Research [328186]
- Movember Discovery Program award
- Department of Defense [11496001]
- PCF-BC grant-in-aid award
- Evelyn Martin Memorial Fellowship
- CIHR
- MSFHR
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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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