1. Academic Validation
  2. 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.
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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