Data from AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function <i>In Vitro</i> and <i>In Vivo</i>

Abstract

<div>Abstract<p>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 <i>in vitro</i> and <i>in vivo</i>. 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 <i>in vivo</i>. AZD3514 is currently in phase I clinical evaluation. <i>Mol Cancer Ther; 12(9); 1715–27. ©2013 AACR</i>.</p></div>