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Differential Targeting of Human Topoisomerase II Isoforms with Small Molecules

Angelica Mariani1, Alexandra Bartoli1, Mandeep Atwal2

  • 1†Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.

Journal of Medicinal Chemistry
|May 7, 2015
PubMed

Insights

Etoposide, a TOP2 poison, can cause secondary cancers. Researchers synthesized etoposide analogues, finding two new molecules that specifically harm TOP2B, aiding cancer research.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • Etoposide is a topoisomerase II (TOP2) poison used in cancer therapy.
  • TOP2 poisons can lead to secondary malignancies.
  • Structural similarities between TOP2 isoforms hinder the development of targeted therapies.

Purpose of the Study:

  • To synthesize and evaluate etoposide analogues.
  • To identify novel small molecules with isoform-specific TOP2 toxicity.
  • To enable the study of TOP2 isoform-specific cellular processes.

Main Methods:

  • Synthesis of a focused library of etoposide analogues.
  • Biological evaluation of synthesized compounds.
  • Assessment of TOP2 isoform-dependent toxicity.

Main Results:

  • Identified two novel small molecules.
  • These compounds exhibit TOP2B-dependent toxicity.
  • Demonstrated the potential for isoform-specific small molecule intervention.

Conclusions:

  • Developed novel etoposide analogues with selective TOP2B toxicity.
  • These molecules can be used to investigate TOP2 isoform functions.
  • Offers a new approach for studying topoisomerase II in cancer treatment and beyond.

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