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Thymidylate synthase as a molecular target for drug discovery using the National Cancer Institute's Anticancer Drug

A L Parr1, T G Myers, S L Holbeck

  • 1Medicine Branch, Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20889, USA. parra@mail.nih.gov

Anti-Cancer Drugs
|August 7, 2001
PubMed

Insights

Researchers identified a new drug cluster selectively killing cancer cells overexpressing thymidylate synthase (TS). This finding offers potential for new cancer therapeutics targeting TS-overexpressing tumors.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Thymidylate synthase (TS) is a key target for cancer chemotherapy, with its overexpression leading to resistance against fluoropyrimidines and antifolates.
  • Developing agents that selectively target TS-overexpressing cancer cells is crucial for overcoming therapeutic resistance.

Purpose of the Study:

  • To identify novel compounds that selectively target cancer cells with high thymidylate synthase (TS) expression.
  • To evaluate the efficacy of identified compounds in a validation assay using cell lines with varying TS expression levels.

Main Methods:

  • A comprehensive screening of 30,000 compounds from the NCI Drug Repository was performed using two algorithms.
  • Cytotoxicity profiles were compared against TS expression levels measured by Western blot in 53 cell lines.
  • A novel COMPARE Effect Clusters analysis was employed to identify selective compounds after traditional COMPARE analysis failed.

Main Results:

  • Traditional COMPARE analysis did not identify compounds selectively killing high TS-expressing cells.
  • The COMPARE Effect Clusters analysis successfully identified a drug cluster with selective cytotoxicity against TS-overexpressing cell lines.
  • The identified compounds' mechanism of action was not direct TS targeting, but TS overexpression served as a marker for sensitivity.

Conclusions:

  • A novel class of compounds selectively kills cancer cells overexpressing thymidylate synthase (TS).
  • These compounds may serve as a basis for developing new therapeutics for cancers characterized by de novo TS overexpression.
  • TS overexpression can act as a predictive biomarker for sensitivity to this newly identified class of cytotoxic agents.

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