2. Academic Validation
  3. AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo

AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo

  • Mol Cancer Ther. 2013 Sep;12(9):1715-27. doi: 10.1158/1535-7163.MCT-12-1174.
Sarah A Loddick 1,  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
Affiliations

Affiliation

  • 1 Corresponding Author: A. Nigel Brooks, Oncology iMED, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. Nigel.Brooks@astrazeneca.com.
PMID: 23861347 DOI: 10.1158/1535-7163.MCT-12-1174
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.

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