Strategy for Tumor-Selective Disruption of Androgen Receptor Function in the Spectrum of Prostate Cancer

Clin Cancer Res. 2018 Dec 15;24(24):6509-6522. doi: 10.1158/1078-0432.CCR-18-0982. Epub 2018 Sep 5.


Purpose: Testosterone suppression in prostate cancer is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for AR-dependent growth in various hormone-dependent and castration-resistant prostate cancer models. The amino-terminal domain of AR docks at two sites on ELK1 to coactivate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1-AR interaction in the spectrum of prostate cancer, inhibiting AR activity in a manner that would predict functional tumor selectivity.

Experimental design: Small-molecule drug discovery and extensive biological characterization of a lead compound.

Results: We have discovered a lead molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant ARs without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl groups on C5 and C3'. KCI807 binds to AR, blocking ELK1 binding, and selectively blocks recruitment of AR to chromatin by ELK1. KCI807 primarily affects a subset of AR target growth genes selectively suppressing AR-dependent growth of prostate cancer cell lines with a better inhibitory profile than enzalutamide. KCI807 also inhibits in vivo growth of castration/enzalutamide-resistant cell line-derived and patient-derived tumor xenografts. In the rodent model, KCI807 has a plasma half-life of 6 hours, and maintenance of its antitumor effect is limited by self-induced metabolism at its 3'-hydroxyl.

Conclusions: The results offer a mechanism-based therapeutic paradigm for disrupting the AR growth-promoting axis in the spectrum of prostate tumors while reducing global suppression of testosterone actions. KCI807 offers a good lead molecule for drug development.

Publication types

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

MeSH terms

  • Androgen Receptor Antagonists / chemistry
  • Androgen Receptor Antagonists / pharmacology*
  • Androgen Receptor Antagonists / therapeutic use
  • Animals
  • Antineoplastic Agents, Hormonal / chemistry
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Discovery / methods
  • Drug Screening Assays, Antitumor
  • Gene Expression Profiling
  • High-Throughput Screening Assays
  • Humans
  • Male
  • Mice
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Binding
  • Receptors, Androgen / metabolism*
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays
  • ets-Domain Protein Elk-1 / metabolism


  • Androgen Receptor Antagonists
  • Antineoplastic Agents, Hormonal
  • ELK1 protein, human
  • Receptors, Androgen
  • ets-Domain Protein Elk-1