"True" antiandrogens-selective non-ligand-binding pocket disruptors of androgen receptor-coactivator interactions: novel tools for prostate cancer

J Med Chem. 2012 Feb 23;55(4):1635-44. doi: 10.1021/jm201438f. Epub 2012 Feb 10.

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 types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / chemical synthesis*
  • Androgen Antagonists / chemistry
  • Androgen Antagonists / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Databases, Factual
  • Drug Screening Assays, Antitumor
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor beta / metabolism
  • Fluorescence Polarization
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Hydrazines / chemical synthesis*
  • Hydrazines / chemistry
  • Hydrazines / pharmacology
  • Male
  • Models, Molecular
  • Nuclear Receptor Coactivators / metabolism*
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Receptors, Androgen / metabolism*
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Progesterone / antagonists & inhibitors
  • Structure-Activity Relationship

Substances

  • Androgen Antagonists
  • Antineoplastic Agents
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Hydrazines
  • Nuclear Receptor Coactivators
  • Receptors, Androgen
  • Receptors, Glucocorticoid
  • Receptors, Progesterone
  • Prostate-Specific Antigen