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Lookup NU author(s): Sarah Jane Ross, Dr Fadhel Shaheen, Dr Luke GaughanORCiD, Professor Craig Robson, Professor Steve Wedge
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Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation. (C) 2013 AACR.
Author(s): Loddick SA, Ross SJ, Thomason AG, Robinson DM, Walker GE, Dunkley TPJ, Brave SR, Broadbent N, Stratton NC, Trueman D, Mouchet E, Shaheen FS, Jacobs VN, Cumberbatch M, Wilson J, Jones RDO, Bradbury RH, Rabow A, Gaughan L, Womack C, Barry ST, Robson CN, Critchlow SE, Wedge SR, Brooks AN
Publication type: Article
Publication status: Published
Journal: Molecular Cancer Therapeutics
Year: 2013
Volume: 12
Issue: 9
Pages: 1715-1727
Print publication date: 16/07/2013
ISSN (print): 1535-7163
ISSN (electronic): 1538-8514
Publisher: American Association for Cancer Research
URL: http://dx.doi.org/10.1158/1535-7163.MCT-12-1174
DOI: 10.1158/1535-7163.MCT-12-1174
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