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Crystal Structure of the N-terminal Domain of Ryanodine Receptor from Plutella xylostella
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Crystal Structure of the N-terminal Domain of Ryanodine Receptor from Plutella xylostella

Published on: November 30, 2018

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Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino-terminal domain

Yaping Hua1, Waqas Azeem1,2, Yunheng Shen3

  • 1Department of Clinical Science University of Bergen Bergen Norway.

Pharmacology Research & Perspectives
|November 10, 2018
PubMed

Insights

A novel compound 154 targets both androgen receptor (AR) and IL6/STAT3 pathways, inhibiting prostate cancer (PCa) growth. This dual-action agent shows promise for treating castration-resistant prostate cancer (CRPC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Prostate cancer (PCa) frequently progresses to castration-resistant prostate cancer (CRPC) after androgen deprivation therapy.
  • Androgen receptor (AR) signaling and the IL6/STAT3 pathway are critical drivers of CRPC.
  • The interplay between AR and IL6/STAT3 pathways presents therapeutic targets for novel agents.

Purpose of the Study:

  • To identify novel natural compounds targeting both AR and IL6/STAT3 pathways in CRPC.
  • To evaluate the efficacy of a specific small molecule, compound 154, as a potential CRPC therapeutic.

Main Methods:

  • Screening of approximately 600 natural compounds using a prostate tumorigenesis model.
  • Assessing compound 154's effects on AR and STAT3 transcriptional activity, phosphorylation, and target gene expression.
  • Investigating compound 154's direct binding to AR and its mechanism of action, including AR amino-terminal domain (NTD) antagonism.

Main Results:

  • Compound 154 demonstrated dual inhibition of AR and STAT3 transcriptional activity.
  • It reduced STAT3 phosphorylation (Y705) and downregulated AR target gene mRNA.
  • Compound 154 inhibited AR and AR splice variants (ARv567es, AR-V7) protein expression, binds directly to AR, and acts as an AR NTD antagonist.

Conclusions:

  • Compound 154 effectively inhibits key pathways driving CRPC.
  • It acts as an AR NTD antagonist by disrupting STAT3-AR NTD interactions without affecting AR nuclear translocation.
  • Compound 154 shows significant potential as a lead compound for developing new CRPC therapies.
Keywords:
STAT3amino‐terminal domainandrogen receptordrug developmentprostate cancer

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