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First identification of small-molecule inhibitors of Pontin by combining virtual screening and enzymatic assay

Judith Elkaim1, Michel Castroviejo, Driss Bennani

  • 1Molecular Modeling Group, IECB-CNRS-Université de Bordeaux, UMR 5248, Pessac, France.

The Biochemical Journal
|January 26, 2012
PubMed

Insights

Researchers identified novel small-molecule inhibitors targeting the human protein Pontin (ATPases associated with various cellular activities), a promising candidate for cancer therapy, particularly for liver cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Pontin, a member of the AAA+ ATPase family, is overexpressed in various cancers, including liver cancer.
  • Pontin's role in tumor cell proliferation and apoptosis makes it a potential therapeutic target.
  • The ATP-binding site of Pontin has been structurally characterized.

Purpose of the Study:

  • To identify small-molecule inhibitors of Pontin's ATPase activity.
  • To discover novel therapeutic agents for cancers with limited treatment options, such as liver cancer.

Main Methods:

  • Structure-based virtual screening of 2200 commercial molecules against Pontin's ATP-binding site using Vina, DrugScore, and Xscore.
  • Development of a colorimetric assay to measure inhibition of Pontin's ATPase activity.
  • Determination of inhibition constants and assessment of anti-proliferative effects of top-scoring compounds.

Main Results:

  • Virtual screening prioritized potential inhibitor candidates.
  • Four ligands demonstrated inhibition of Pontin's ATPase activity with micromolar inhibition constants.
  • Three of these identified compounds exhibited anti-tumorigenic effects on cancer cell proliferation.

Conclusions:

  • The combined approach of virtual screening and experimental assays successfully identified the first small-molecule inhibitors of Pontin.
  • These findings offer a promising starting point for developing novel cancer therapeutics targeting Pontin.

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