| Literature DB >> 23861347 |
Sarah A Loddick1, Sarah J Ross, Andrew G Thomason, David M Robinson, Graeme E Walker, Tom P J Dunkley, Sandra R Brave, Nicola Broadbent, Natalie C Stratton, Dawn Trueman, Elizabeth Mouchet, Fadhel S Shaheen, Vivien N Jacobs, Marie Cumberbatch, Joanne Wilson, Rhys D O Jones, Robert H Bradbury, Alfred Rabow, Luke Gaughan, Chris Womack, Simon T Barry, Craig N Robson, Susan E Critchlow, Stephen R Wedge, A Nigel Brooks.
Abstract
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.Entities:
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Year: 2013 PMID： 23861347 PMCID： PMC3769207 DOI： 10.1158/1535-7163.MCT-12-1174
Source DB: PubMed Journal: Mol Cancer Ther ISSN： 1535-7163 Impact factor: 6.261