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

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 year

  2019

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2019-12-05

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.jmedchem.9b01393PMID 31804827
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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