Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor

Cancer Cell. 2010 Jun 15;17(6):535-46. doi: 10.1016/j.ccr.2010.04.027.

Abstract

Castration-recurrent prostate cancer (CRPC) is suspected to depend on androgen receptor (AR). The AF-1 region in the amino-terminal domain (NTD) of AR contains most, if not all, of the transcriptional activity. Here we identify EPI-001, a small molecule that blocked transactivation of the NTD and was specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors. EPI-001 interacted with the AF-1 region, inhibited protein-protein interactions with AR, and reduced AR interaction with androgen-response elements on target genes. Importantly, EPI-001 blocked androgen-induced proliferation and caused cytoreduction of CRPC in xenografts dependent on AR for growth and survival without causing toxicity.

Publication types

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

MeSH terms

  • Androgen Receptor Antagonists*
  • Androgens / pharmacology
  • Animals
  • Antineoplastic Agents, Hormonal / adverse effects
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Apoptosis / drug effects
  • Benzhydryl Compounds / adverse effects
  • Benzhydryl Compounds / pharmacology
  • Benzhydryl Compounds / therapeutic use*
  • CREB-Binding Protein / metabolism
  • Castration*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chlorohydrins / adverse effects
  • Chlorohydrins / pharmacology
  • Chlorohydrins / therapeutic use*
  • DNA / genetics
  • DNA / metabolism
  • Gene Expression / drug effects
  • Humans
  • Ligands
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Structure
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Prostate / anatomy & histology
  • Prostate / drug effects
  • Prostate / pathology
  • Prostate-Specific Antigen / blood
  • Prostate-Specific Antigen / genetics
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / surgery
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Protein Conformation / drug effects
  • Protein Interaction Domains and Motifs / drug effects
  • Protein Multimerization / drug effects
  • Receptors, Androgen / metabolism
  • Receptors, Steroid / drug effects
  • Response Elements / genetics
  • Serine Endopeptidases / genetics
  • Transcriptional Activation / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Androgen Receptor Antagonists
  • Androgens
  • Antineoplastic Agents, Hormonal
  • Benzhydryl Compounds
  • Chlorohydrins
  • EPI 001
  • Ligands
  • Receptors, Androgen
  • Receptors, Steroid
  • DNA
  • CREB-Binding Protein
  • CREBBP protein, human
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • Prostate-Specific Antigen