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
  • 1. Corresponding Author: A. Nigel Brooks, Oncology iMED, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. [email protected].
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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