A competitive inhibitor that reduces recruitment of androgen receptor to androgen-responsive genes

J Biol Chem. 2012 Jul 6;287(28):23368-80. doi: 10.1074/jbc.M112.344671. Epub 2012 May 15.

Abstract

The androgen receptor (AR) has a critical role in the growth and progression of androgen-dependent and castration-resistant prostate cancers. To identify novel inhibitors of AR transactivation that block growth of prostate cancer cells, a luciferase-based high-throughput screen of ~160,000 small molecules was performed in cells stably expressing AR and a prostate-specific antigen (PSA)-luciferase reporter. CPIC (1-(3-(2-chlorophenoxy) propyl)-1H-indole-3-carbonitrile) was identified as a small molecule that blocks AR transactivation to a greater extent than other steroid receptors. CPIC inhibited AR-mediated proliferation of androgen-sensitive prostate cancer cell lines, with minimal toxicity in AR-negative cell lines. CPIC treatment also reduced the anchorage-independent growth of LAPC-4 prostate cancer cells. CPIC functioned as a pure antagonist by inhibiting the expression of AR-regulated genes in LAPC-4 cells that express wild-type AR and exhibited weak agonist activity in LNCaP cells that express the mutant AR-T877A. CPIC treatment did not reduce AR levels or alter its nuclear localization. We used chromatin immunoprecipitation to identify the site of action of CPIC. CPIC inhibited recruitment of androgen-bound AR to the PSA promoter and enhancer sites to a greater extent than bicalutamide. CPIC is a new therapeutic inhibitor that targets AR-mediated gene activation with potential to arrest the growth of prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Receptor Antagonists / metabolism
  • Androgen Receptor Antagonists / pharmacology*
  • Androgens / metabolism
  • Androgens / pharmacology*
  • Anilides / pharmacology
  • Binding, Competitive
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Neoplastic / drug effects*
  • HeLa Cells
  • Humans
  • Indoles / metabolism
  • Indoles / pharmacology
  • Luciferases / genetics
  • Luciferases / metabolism
  • Male
  • Metribolone / metabolism
  • Metribolone / pharmacology
  • Microscopy, Fluorescence
  • Nitriles / pharmacology
  • Prostate-Specific Antigen / genetics
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Small Molecule Libraries
  • Tosyl Compounds / pharmacology

Substances

  • 1-(3-(2-chlorophenoxy)propyl)-1H-indole-3-carbonitrile
  • Androgen Receptor Antagonists
  • Androgens
  • Anilides
  • Indoles
  • Nitriles
  • Receptors, Androgen
  • Small Molecule Libraries
  • Tosyl Compounds
  • Metribolone
  • bicalutamide
  • Luciferases
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • Prostate-Specific Antigen