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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known

Karita Peltonen1, Laureen Colis, Hester Liu

  • 1Molecular Cancer Biology Program and Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland.

Plos One
|October 2, 2010
PubMed

Insights

Researchers screened small molecules to activate the p53 tumor suppressor pathway, identifying six novel compounds that inhibit human cancer cell growth. Two compounds showed efficacy in a lymphoma mouse model, highlighting DNA topology interference as a key activation mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The p53 tumor suppressor pathway is a critical target for cancer therapy.
  • Previous studies show manipulating p53 activity benefits preclinical models and has entered clinical trials.

Purpose of the Study:

  • To identify novel small-molecule compounds that activate the p53 pathway and exhibit potent antitumor activity.
  • To explore new therapeutic strategies for human cancers by targeting p53.

Main Methods:

  • Conducted an extensive small-molecule chemical compound library screen in a human cancer cell line.
  • Evaluated compound efficacy in vitro and in an orthotopic mouse model of human B-cell lymphoma.
  • Analyzed compound interactions with DNA and gene-expression signatures.

Main Results:

  • Discovered six novel small-molecule lead compounds that activate p53 and inhibit human cancer cell growth.
  • Two compounds demonstrated suppression of in vivo tumor growth in a lymphoma model.
  • Identified DNA interaction and interference with DNA topology as a primary mechanism for p53 pathway activation.

Conclusions:

  • The screen successfully identified potent novel antitumor agents targeting the p53 pathway.
  • Interference with DNA topology is a predominant mechanism for pharmacological p53 activation.
  • Unexpected drug classes, including neuroleptics and antihistamines, showed potential anticancer activity through p53 activation.

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