Caboni, Laura and Kinsella, Gemma K. and Blanco, Fernando and Fayne, Darren and Jagoe, William M. and Carr, Miriam and Williams, D. Clive and Meegan, Mary J. and Lloyd, David G. (2012) “True” Antiandrogens : Selective Non-Ligand-Binding Pocket Disruptors of Androgen Receptor−Coactivator Interactions: Novel Tools for Prostate Cancer. Journal of Medicinal Chemistry, 55. pp. 1635-1644. ISSN 0022-2623

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Abstract

Prostate cancer (PCa) therapy typically involves administration of “classical” antiandrogens, competitive inhibitors of androgen receptor (AR) ligands, dihydrotestosterone (DHT) and testosterone (tes), for the ligand-binding pocket (LBP) in the ligand-binding domain (LBD) of AR. Prolonged LBP-targeting leads to resistance, and alternative therapies are urgently required. We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and ligand-based virtual screening. Compounds demonstrate full (“true”) antagonism in AR with low micromolar potency, selectivity over estrogen receptors α and β and glucocorticoid receptor, and partial antagonism of the progesterone receptor. MDG506 (5) demonstrates low cellular toxicity in PCa models and dose responsive reduction of classical antiandrogen-induced prostate specific antigen expression. These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.

Item Type:	Article
Keywords:	True Antiandrogens; Selective; Non-Ligand-Binding; Pocket Disruptors; Androgen; Receptor−Coactivator; Interactions; Prostate Cancer;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	5432
Identification Number:	dx.doi.org/10.1021/jm201438f
Depositing User:	Gemma Kinsella
Date Deposited:	29 Sep 2014 15:08
Journal or Publication Title:	Journal of Medicinal Chemistry
Publisher:	ACS Publications
Refereed:	Yes
URI:	http://pubs.acs.org/loi/jmcmar
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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