The androgen receptor in prostate cancer: Effect of structure, ligands and spliced variants on therapy

Elisabeth A. Messner, Thomas M. Steele, Maria Malvina Tsamouri, Nazila Hejazi, Allen C. Gao, Maria Mudryj, Paramita M. Ghosh

Research output: Contribution to journalReview articlepeer-review

8 Scopus citations

Abstract

The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand binding at the LBD promotes AR dimerization and translocation to the nucleus where the DBD binds target DNA. In PCa, AR signaling is perturbed by excessive androgen synthesis, AR amplification, mutation, or the formation of AR alternatively spliced variants (AR-V) that lack the LBD. Current therapies for advanced PCa include androgen synthesis inhibitors that suppress T and/or DHT synthesis, and AR inhibitors that prevent ligand binding at the LBD. However, AR mutations and AR-Vs render LBD-specific therapeutics ineffective. The DBD and NTD are novel targets for inhibition as both perform necessary roles in AR transcriptional activity and are less susceptible to AR alternative splicing compared to the LBD. DBD and NTD inhibition can potentially extend patient survival, improve quality of life, and overcome predominant mechanisms of resistance to current therapies. This review discusses various small molecule and other inhibitors developed against the DBD and NTD—and the current state of the available compounds in clinical development.

Original languageEnglish (US)
Article number422
Pages (from-to)1-19
Number of pages19
JournalBiomedicines
Volume8
Issue number10
DOIs
StatePublished - Oct 2020

Keywords

  • Alternatively spliced variants
  • Androgen receptor
  • Castration-resistant prostate cancer
  • DNA-binding domain
  • Ligand-binding domain
  • N-terminal domain

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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