Supplementary Materials and Methods from AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

Loddick, Sarah A.; Ross, Sarah J.; Thomason, Andrew G.; Robinson, David M.; Walker, Graeme E.; Dunkley, Tom P.J.; Brave, Sandra R.; Broadbent, Nicola; Stratton, Natalie C.; Trueman, Dawn; Mouchet, Elizabeth; Shaheen, Fadhel S.; Jacobs, Vivien N.; Cumberbatch, Marie; Wilson, Joanne; Jones, Rhys D.O.; Bradbury, Robert H.; Rabow, Alfred; Gaughan, Luke; Womack, Chris; Barry, Simon T.; Robson, Craig N.; Critchlow, Susan E.; Wedge, Stephen R.; Brooks, A. Nigel

doi:10.1158/1535-7163.22500958.v1

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Supplementary Materials and Methods from AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

journal contribution

posted on 2023-04-03, 14:10 authored by Sarah A. Loddick, 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

PDF - 56KB, Supplementary methods detailing Relative peptide quantification by selected reaction monitoring (SRM)using mass spectrometry

History

ARTICLE 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. Mol Cancer Ther; 12(9); 1715–27. ©2013 AACR.