Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Neoplasm
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Cells, Cultured
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DNA Topoisomerases, Type II
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DNA-Binding Proteins / antagonists & inhibitors*
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Etoposide / analogs & derivatives*
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Humans
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Leukemia / drug therapy
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Leukemia / enzymology
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Mice
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Mice, Knockout
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Models, Molecular
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Molecular Structure
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Poly-ADP-Ribose Binding Proteins
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Topoisomerase II Inhibitors / chemistry
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Topoisomerase II Inhibitors / pharmacology*
Substances
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Antigens, Neoplasm
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DNA-Binding Proteins
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Poly-ADP-Ribose Binding Proteins
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Small Molecule Libraries
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Topoisomerase II Inhibitors
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Etoposide
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DNA Topoisomerases, Type II
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TOP2A protein, human
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TOP2B protein, human
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Top2a protein, mouse
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Top2b protein, mouse