作者
Nicola J Clegg, John Wongvipat, James D Joseph, Chris Tran, Samedy Ouk, Anna Dilhas, Yu Chen, Kate Grillot, Eric D Bischoff, Ling Cai, Anna Aparicio, Steven Dorow, Vivek Arora, Gang Shao, Jing Qian, Hong Zhao, Guangbin Yang, Chunyan Cao, John Sensintaffar, Teresa Wasielewska, Mark R Herbert, Celine Bonnefous, Beatrice Darimont, Howard I Scher, Peter Smith-Jones, Mark Klang, Nicholas D Smith, Elisa De Stanchina, Nian Wu, Ouathek Ouerfelli, Peter J Rix, Richard A Heyman, Michael E Jung, Charles L Sawyers, Jeffrey H Hager
发表日期
2012/3/15
期刊
Cancer research
卷号
72
期号
6
页码范围
1494-1503
出版商
American Association for Cancer Research
简介
Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway–targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of …
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NJ Clegg, J Wongvipat, JD Joseph, C Tran, S Ouk… - Cancer research, 2012