title: A competitive inhibitor that reduces recruitment of androgen receptor to androgen-responsive genes.
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.
authors.affiliation: Department of Biochemistry,University of Illinois, Urbana, Illinois 61801-3602, USA.
authors.forename: Milu T
authors.initials: MT
authors.lastname: Cherian
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
authors.forename: David J
authors.initials: DJ
authors.lastname: Shapiro
mesh_terms: D059002:Androgen Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D001667:Binding, Competitive; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D015741:Metribolone / Q000378:metabolism / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009570:Nitriles / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: C575381:1-(3-(2-chlorophenoxy)propyl)-1H-indole-3-carbonitrile; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D007211:Indoles; D009570:Nitriles; D011944:Receptors, Androgen; D054852:Small Molecule Libraries; D014105:Tosyl Compounds; D015741:Metribolone; C053541:bicalutamide; D008156:Luciferases; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D017430:Prostate-Specific Antigen