Selectively Targeting the Dimerization Interface of Human Androgen Receptor With Small-Molecules to Treat Castration-Resistant Prostate Cancer

Cancer Lett. 2018 Nov 28;437:35-43. doi: 10.1016/j.canlet.2018.08.016. Epub 2018 Aug 27.


Prostate cancer (PCa) is a leading cause of death for men in North America. The androgen receptor (AR) - a hormone inducible transcription factor - drives expression of tumor promoting genes and represents an important therapeutic target in PCa. The AR is activated by steroid recruitment to its ligand binding domain (LBD), followed by receptor nuclear translocation and dimerization via the DNA binding domain (DBD). Clinically used small molecules interfere with steroid recruitment and prevent AR-driven tumor growth, but are rendered ineffective by emergence of LBD mutations or expression of constitutively active variants, such as ARV7, that lack the LBD. Both drug-resistance mechanisms confound treatment of this 'castration resistant' stage of PCa (CRPC), characterized by return of AR signalling. Here, we employ computer-aided drug-design to develop small molecules that block the AR-DBD dimerization interface, an attractive target given its role in AR activation and independence from the LBD. Virtual screening on the AR-DBD structure led to development of prototypical compounds that block AR dimerization, inhibiting AR-transcriptional activity through a LBD-independent mechanism. Such inhibitors may potentially circumvent AR-dependent resistance mechanisms and directly target CRPC tumor growth.

Keywords: Androgen receptor; Dimerization; Prostate cancer; Small molecule inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites / genetics
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • HEK293 Cells
  • Humans
  • Imidazoles / metabolism
  • Imidazoles / pharmacology
  • Male
  • Mutation
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Protein Domains
  • Protein Multimerization / drug effects*
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Sequence Homology, Amino Acid
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*
  • Thiazoles / metabolism
  • Thiazoles / pharmacology


  • 4-(4-(4,5-bromo-1H-imidazol-1-yl)thiazol-2-yl)morpholine
  • Imidazoles
  • Receptors, Androgen
  • Small Molecule Libraries
  • Thiazoles

Grant support