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Small Molecule, NSC95397, Inhibits the CtBP1-Protein Partner Interaction and CtBP1-Mediated Transcriptional

Melanie A Blevins1, Jennifer Kouznetsova2, Aaron B Krueger1

  • 1Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA.

Journal of Biomolecular Screening
|December 6, 2014
PubMed

Insights

Carboxyl-terminal binding protein (CtBP) is a cancer-promoting factor. Researchers identified a compound, NSC95397, that inhibits CtBP activity, offering a potential new cancer therapy by disrupting cancer cell survival mechanisms.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • Carboxyl-terminal binding protein (CtBP) is a transcriptional corepressor overexpressed in many human cancers.
  • CtBP overexpression promotes cancer progression by enhancing stem cell-like features, epithelial-mesenchymal transition, and cell survival.
  • CtBP knockdown induces apoptosis, suggesting its potential as a therapeutic target.

Purpose of the Study:

  • To identify small molecules that inhibit the interaction between CtBP and its transcriptional partners.
  • To explore the potential of disrupting the CtBP transcriptional complex as a cancer therapy.

Main Methods:

  • Development of an AlphaScreen high-throughput screening assay to monitor CtBP-E1A interaction.
  • Screening of the LOPAC library of 1280 bioactive compounds.
  • Confirmation of inhibitory activity using secondary assays and a counterscreen.
  • Assessment of NSC95397's effect on CtBP-mediated transcriptional repression.

Main Results:

  • Identification of NSC95397 as an inhibitor of the CtBP-E1A interaction with an IC50 of 2.9 µM.
  • Confirmation of NSC95397's inhibitory activity and specificity.
  • Demonstration that NSC95397 disrupts CtBP-mediated transcriptional repression of a target gene.

Conclusions:

  • NSC95397 is a novel inhibitor of the CtBP transcriptional complex.
  • Disrupting the CtBP transcriptional complex presents a promising strategy for cancer therapy.
  • Further development of NSC95397 or similar compounds could lead to new anti-cancer agents.
Keywords:
AlphaScreenCtBP1E1ANSC95397protein-protein interaction

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