Small molecule-induced degradation of the full length and V7 truncated variant forms of human androgen receptor

Eur J Med Chem. 2018 Sep 5;157:1164-1173. doi: 10.1016/j.ejmech.2018.08.059. Epub 2018 Aug 24.


The androgen receptor (AR) is a hormone-activated transcription factor that regulates the development and progression of prostate cancer (PCa) and represents one of the most well-established drug targets. Currently clinically approved small molecule inhibitors of AR, such as enzalutamide, are built upon a common chemical scaffold that interacts with the AR by the same mechanism of action. These inhibitors eventually fail due to the emergence of drug-resistance in the form of AR mutations and expression of truncated AR splice variants (e.g. AR-V7) that are constitutively active, signalling the progression of the castration-resistant state of the disease. The urgent need therefore continues for novel classes of AR inhibitors that can overcome drug resistance, especially since AR signalling remains important even in late-stage advanced PCa. Previously, we identified a collection of 10-benzylidene-10H-anthracen-9-ones that effectively inhibit AR transcriptional activity, induce AR degradation and display some ability to block recruitment of hormones to the receptor. In the current work, we extended the analysis of the lead compounds, and used methods of both ligand- and structure-based drug design to develop a panel of novel 10-benzylidene-10H-anthracen-9-one derivatives capable of suppressing transcriptional activity and protein expression levels of both full length- and AR-V7 truncated forms of human androgen receptor. Importantly, the developed compounds efficiently inhibited the growth of AR-V7 dependent prostate cancer cell-lines which are completely resistant to all current anti-androgens.

Keywords: ARV7; Androgen receptor; Prostate cancer; Protein degradation; Small-molecules.

MeSH terms

  • Androgen Antagonists / chemical synthesis
  • Androgen Antagonists / chemistry
  • Androgen Antagonists / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Genetic Variation / genetics*
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • AR protein, human
  • Androgen Antagonists
  • Receptors, Androgen
  • Small Molecule Libraries