title: Differential Targeting of Human Topoisomerase II Isoforms with Small Molecules.
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.
authors.affiliation: †Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Angelica
authors.initials: A
authors.lastname: Mariani
authors.affiliation: †Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bartoli
authors.affiliation: ‡Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Mandeep
authors.initials: M
authors.lastname: Atwal
authors.affiliation: ‡Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Ka C
authors.initials: KC
authors.lastname: Lee
authors.affiliation: ‡Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Austin
authors.affiliation: †Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.|§Organic Synthesis and Cell Biology Group, Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm; D002478:Cells, Cultured; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D005047:Etoposide / Q000031:analogs & derivatives*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D000075223:Poly-ADP-Ribose Binding Proteins; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D054852:Small Molecule Libraries; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618814:TOP2B protein, human; C000618812:Top2a protein, mouse; C000618815:Top2b protein, mouse