Structural Based Screening of Antiandrogen Targeting Activation Function-2 Binding Site

• Main Authors: Yangguang Liu, Meng Wu, Tianqi Wang, Yongli Xie, Xiangling Cui, Liujun He, Yang He, Xiaoyu Li, Mingliang Liu, Laixing Hu, Shan Cen, Jinming Zhou
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2018-11-01
• Series: Frontiers in Pharmacology
• Subjects: androgen receptor; structural based drug design; antiandrogen; castration-resistant prostate cancer; activation function-2
• Online Access: https://www.frontiersin.org/article/10.3389/fphar.2018.01419/full

Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). Current antiandrogen therapies induce resistant mutations at the hormone binding pocket (HBP) that convert the activity of these agents from antagonist to agonist. Thus, there is a high unmet medical need for the development of novel antiandrogens which circumvent mutation-based resistance. Herein, through the analysis of AR structures with ligands binding to the activation function-2 (AF2) site, we built a combined pharmacophore model. In silico screening and the subsequent biological evaluation lead to the discovery of the novel lead compound IMB-A6 that binds to the AF2 site, which inhibits the activity of either wild-type (WT) or resistance mutated ARs. Our work demonstrates structure-based drug design is an efficient strategy to discover new antiandrogens, and provides a new class of small molecular antiandrogens for the development of novel treatment agents against PCa.