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Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer
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Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer

Miriam S Butler1, Mani Roshan-Moniri1, Michael Hsing1

  • 1Vancouver Prostate Centre and the Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.

Oncotarget
|May 4, 2017
PubMed

Insights

Scientists developed new small molecule ERG antagonists to treat prostate cancer. These compounds block the ERG-ETS domain, reducing cancer cell invasion and metastasis, offering potential new therapies for ERG-expressing prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Genomic alterations, specifically translocations of the ETS-related gene ERG, are found in about half of prostate cancer cases.
  • These alterations lead to abnormal ERG protein production, driving prostate cancer development and progression.
  • ERG protein is a key driver in ERG-positive prostate cancers.

Purpose of the Study:

  • To discover and characterize novel small molecule ERG antagonists.
  • To investigate the potential of these antagonists in inhibiting ERG's transcriptional activity and reversing cancer cell characteristics.
  • To evaluate the therapeutic potential of targeting the ERG-ETS domain in prostate cancer.

Main Methods:

  • Rational in silico drug design to identify ERG antagonists.
  • Biophysical methods to confirm compound binding to the ERG-ETS domain.
  • In vitro assays to assess the effect of compounds on prostate cancer cell migration and invasion.
  • Zebrafish xenograft models to evaluate anti-metastatic effects.

Main Results:

  • Discovery of a new class of small molecule ERG antagonists.
  • Confirmation of direct binding of lead compound VPC-18005 to the ERG-ETS domain.
  • VPC-18005 significantly reduced migration and invasion of ERG-expressing prostate cancer cells.
  • VPC-18005 demonstrated reduced metastasis in a zebrafish xenograft model.

Conclusions:

  • Small molecule targeting of the ERG-ETS domain can suppress transcriptional activity.
  • Targeting the ERG-ETS domain can reverse transformed characteristics in ERG-expressing prostate cancers.
  • Developed small molecule inhibitors show promise as novel therapeutic agents for ERG-positive metastatic castration-resistant prostate cancer.
Keywords:
ERGTMPRSS2-ERGprostate cancerrational drug designsmall molecule inhibitor

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