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"True" Antiandrogens-Selective Non-Ligand-Binding Pocket Disruptors of Androgen Receptor-Coactivator Interactions: Novel Tools for Prostate Cancer
J Med Chem (2012)
  • Gemma K Kinsella, Dr, National University of Ireland, Maynooth
  • Laura Caboni, Dr
  • Fernando Blanco, Dr
  • Darren Fayne, Dr
  • William N Jagoe
  • Miriam Carr, Dr
  • D C Williams, Prof
  • Mary J Meegan, Prof
  • David G Lloyd, Dr
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.

Publication Date
Winter January 26, 2012
Citation Information
Gemma K Kinsella, Laura Caboni, Fernando Blanco, Darren Fayne, et al.. ""True" Antiandrogens-Selective Non-Ligand-Binding Pocket Disruptors of Androgen Receptor-Coactivator Interactions: Novel Tools for Prostate Cancer" J Med Chem Vol. 55 Iss. 4 (2012)
Available at: http://works.bepress.com/gemma_kinsella/5/