Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands

J Med Chem. 2019 Dec 26;62(24):11218-11231. doi: 10.1021/acs.jmedchem.9b01393. Epub 2019 Dec 5.


Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization of highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using a potent AR antagonist and E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in the discovery of 11 (ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC50 values of 0.2-1 nM. ARD-266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression. For the first time, we demonstrated that an E3 ligand with micromolar binding affinity to its E3 ligase complex can be successfully employed for the design of highly potent and efficient PROTAC degraders and this finding may have a significant implication for the field of PROTAC research.

Publication types

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

MeSH terms

  • Androgen Receptor Antagonists / chemistry
  • Androgen Receptor Antagonists / pharmacology*
  • Cell Proliferation
  • Drug Design
  • Drug Discovery*
  • Humans
  • Ligands
  • Male
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Proteasome Endopeptidase Complex / drug effects
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis / drug effects*
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Tumor Cells, Cultured
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*


  • AR protein, human
  • Androgen Receptor Antagonists
  • Ligands
  • Piperidines
  • Receptors, Androgen
  • Small Molecule Libraries
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Proteasome Endopeptidase Complex
  • VHL protein, human