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Targeting Binding Function-3 of the Androgen Receptor Blocks Its Co-Chaperone Interactions, Nuclear Translocation,

Nada Lallous1, Eric Leblanc1, Ravi S N Munuganti1

  • 1Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.

Molecular Cancer Therapeutics
|October 22, 2016
PubMed

Insights

Targeting the androgen receptor's Binding Function 3 (BF3) pocket with VPC-13566 shows promise for treating castration-resistant prostate cancer (CRPC). This approach inhibits tumor growth and blocks receptor nuclear translocation, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Advanced prostate cancer often progresses to castration-resistant prostate cancer (CRPC) despite treatments like enzalutamide and abiraterone.
  • Drug resistance and tumor cell survival necessitate novel therapeutic agents for CRPC.
  • Targeting the androgen receptor (AR) Binding Function 3 (BF3) pocket is a potential strategy for CRPC treatment.

Purpose of the Study:

  • To investigate the functional activity of the AR BF3 pocket using a specific small molecule inhibitor, VPC-13566.
  • To evaluate the efficacy of VPC-13566 in preclinical models of prostate cancer, including enzalutamide-resistant forms.
  • To identify AR-BF3 interacting partners and elucidate the mechanism of AR inhibition via BF3.

Main Methods:

  • Utilized VPC-13566, a small molecule inhibitor targeting the AR BF3 pocket.
  • Assessed the effect of VPC-13566 on prostate cancer cell line growth in vitro.
  • Evaluated VPC-13566 efficacy in AR-dependent prostate cancer xenograft models in mice.
  • Employed VPC-13566 as a chemical probe to identify interacting proteins and study AR translocation.

Main Results:

  • VPC-13566 inhibited the growth of various prostate cancer cell lines, including enzalutamide-resistant ones.
  • VPC-13566 reduced the growth of AR-dependent prostate cancer xenograft tumors in vivo.
  • Identified small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA) as an AR-BF3 interacting partner.
  • Demonstrated that BF3 inhibition by VPC-13566 blocks AR nuclear translocation.

Conclusions:

  • Targeting the AR BF3 pocket with small molecules like VPC-13566 is a promising therapeutic strategy for CRPC.
  • Inhibition of AR activity via the BF3 pocket can effectively block receptor nuclear translocation.
  • This study provides novel insights into the functional role of the AR BF3 pocket and its potential clinical importance in CRPC treatment.

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