AR inhibitors identified by high-throughput microscopy detection of conformational change and subcellular localization

Jeremy O. Jones, W. Frank An, Marc I. Diamond

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Signaling via the androgen receptor (AR) plays an important role in human health and disease. All currently available anti-androgens prevent ligand access to the receptor, either by limiting androgen synthesis or by competitive antagonism at the ligand binding domain. It is unknown to what extent various steps of receptor activation may be separable and distinctly targeted by inhibitors. We have previously described the use of fluorescent protein fusions to AR to monitor its subcellular distribution and ligand-induced conformational change by fluorescence resonance energy transfer (FRET). We have now used a microscopy-based screen to identify inhibitors that prevent AR conformational change or nuclear accumulation after ligand activation. Hits were secondarily selected on the basis of their ability to inhibit AR transcription at a PSA-luciferase promoter and were tested for effects on 3H-DHT binding to AR in cells. We find a strong correlation between compounds that block DHT binding and those that inhibit nuclear accumulation. These compounds are structurally distinct from known antagonists. Additional compounds blocked AR conformational change but did not affect DHT binding or nuclear localization of AR. One compound increased ligand-induced FRET yet functioned as a potent inhibitor. These results suggest that multiple inhibitory conformations of AR are possible and can be induced by diverse mechanisms. The lead compounds described here may be candidates for the development of novel anti- androgens and may help identify new therapeutic targets.

Original languageEnglish (US)
Pages (from-to)199-208
Number of pages10
JournalACS chemical biology
Issue number3
StatePublished - Mar 20 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine


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