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AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

Lookup NU author(s): Sarah Jane Ross, Dr Fadhel Shaheen, Dr Luke Gaughan, Professor Craig Robson, Professor Steve Wedge

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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. (C) 2013 AACR.


Publication metadata

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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