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

作者：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^*

来源：Molecular Cancer Therapeutics, 2013, 12(9): 1715-1727.

DOI：10.1158/1535-7163.MCT-12-1174

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.

• 出版日期2013-9