Peptidomimetic targeting of critical androgen receptor-coregulator interactions in prostate cancer

Nat Commun. 2013:4:1923. doi: 10.1038/ncomms2912.

Abstract

The growth of advanced prostate cancer depends on androgen receptor signalling, however treatment options are limited. Here we report the disruption of specific protein-protein interactions involving LXXLL motifs in androgen receptor-coregulator proteins such as PELP1 using a novel, small molecule peptidomimetic (D2). D2 is stable, non-toxic and efficiently taken up by prostate cancer cells. Importantly, D2 blocks androgen-induced nuclear uptake and genomic activity of the androgen receptor. Furthermore, D2 abrogates androgen-induced proliferation of prostate cancer cells in vitro with an IC50 of 40 nM, and inhibits tumour growth in a mouse xenograft model. D2 also disrupts androgen receptor-coregulator interactions in ex vivo cultures of primary human prostate tumours. These findings provide evidence that targeting androgen receptor-coregulator interactions using peptidomimetics may be a viable therapeutic approach for patients with advanced prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Co-Repressor Proteins / metabolism*
  • Humans
  • Male
  • Mice
  • Microscopy, Fluorescence
  • Models, Molecular
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology*
  • Prostatectomy
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / surgery
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Protein Transport / drug effects
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / metabolism*
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • AR protein, human
  • Co-Repressor Proteins
  • PELP1 protein, human
  • Peptidomimetics
  • Receptors, Androgen
  • Transcription Factors

Associated data

  • PubChem-Substance/162169954
  • PubChem-Substance/162169955
  • PubChem-Substance/162169956
  • PubChem-Substance/162169957
  • PubChem-Substance/162169958
  • PubChem-Substance/162169959
  • PubChem-Substance/162169960
  • PubChem-Substance/162169961
  • PubChem-Substance/162169962
  • PubChem-Substance/162169963
  • PubChem-Substance/162169964
  • PubChem-Substance/162169965
  • PubChem-Substance/162169966