Differential Targeting of Human Topoisomerase II Isoforms with Small Molecules

J Med Chem. 2015 Jun 11;58(11):4851-6. doi: 10.1021/acs.jmedchem.5b00473. Epub 2015 May 20.


The TOP2 poison etoposide has been implicated in the generation of secondary malignancies during cancer treatment. Structural similarities between TOP2 isoforms challenge the rational design of isoform-specific poisons to further delineate these processes. Herein, we describe the synthesis and biological evaluation of a focused library of etoposide analogues, with the identification of two novel small molecules exhibiting TOP2B-dependent toxicity. Our findings pave the way toward studying isoform-specific cellular processes by means of small molecule intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm
  • Cells, Cultured
  • DNA Topoisomerases, Type II
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Etoposide / analogs & derivatives*
  • Humans
  • Leukemia / drug therapy
  • Leukemia / enzymology
  • Mice
  • Mice, Knockout
  • Models, Molecular
  • Molecular Structure
  • Poly-ADP-Ribose Binding Proteins
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*


  • Antigens, Neoplasm
  • DNA-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Small Molecule Libraries
  • Topoisomerase II Inhibitors
  • Etoposide
  • DNA Topoisomerases, Type II
  • TOP2A protein, human
  • TOP2B protein, human
  • Top2a protein, mouse
  • Top2b protein, mouse