Targeting the N-Terminal Domain of the Androgen Receptor: A New Approach for the Treatment of Advanced Prostate Cancer

Oncologist. 2016 Dec;21(12):1427-1435. doi: 10.1634/theoncologist.2016-0161. Epub 2016 Sep 14.


: Despite the recent approval and widespread use of abiraterone acetate and enzalutamide for the treatment of castration-resistant prostate cancer (CRPC), this disease still poses significant management challenges because of various tumor escape mechanisms, including those that allow androgen receptor (AR) signaling to remain active. These AR-related resistance mechanisms include AR gene amplification or overexpression, constitutively active ligand-independent AR splice variants, and gain-of-function mutations involving the AR ligand-binding domain (LBD), among others. Therefore, the development of AR-targeted therapies that function independently of the LBD represents an unmet medical need and has the potential to overcome many of these resistance mechanisms. This article discusses N-terminal domain (NTD) inhibition as a novel concept in the field of AR-directed therapies for prostate cancer. AR NTD-targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR-mediated transcriptional activity, and as a result, may affect a broader AR population including mutational and splice variant ARs. Indeed, the first clinical trial of an AR NTD inhibitor is now underway.

Implications for practice: Because of emerging resistance mechanisms that involve the ligand-binding domain of the androgen receptor (AR), there is currently no effective treatment addressing tumor escape mechanisms related to current AR-targeted therapies. Many patients still demonstrate limited clinical response to current hormonal agents, and castration-resistant prostate cancer remains a lethal disease. Intense research efforts are under way to develop therapies to target resistance mechanisms, including those directed at other parts of the AR molecule. A novel small-molecule agent, EPI-506, represents a new pharmaceutical class, AR N-terminal domain inhibitors, and shows preclinical promise to overcome many known resistance mechanisms related to novel hormonal therapies.

Keywords: Androgen receptor; EPI-506; N-terminal domain; Prostate cancer.

Publication types

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

MeSH terms

  • Androgen Antagonists / therapeutic use*
  • Benzhydryl Compounds / therapeutic use*
  • Chlorohydrins / therapeutic use*
  • Humans
  • Male
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Protein Domains
  • Receptors, Androgen / chemistry*
  • Receptors, Androgen / physiology
  • Retrospective Studies
  • Signal Transduction
  • Steroid 17-alpha-Hydroxylase / antagonists & inhibitors


  • AR protein, human
  • Androgen Antagonists
  • Benzhydryl Compounds
  • Chlorohydrins
  • EPI-506
  • Receptors, Androgen
  • Steroid 17-alpha-Hydroxylase