Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue.

BMC Chemical Biology
Patrick ChèneThomas Radimerski

Abstract

Topoisomerase II poisons are in clinical use as anti-cancer therapy for decades and work by stabilizing the enzyme-induced DNA breaks. In contrast, catalytic inhibitors block the enzyme before DNA scission. Although several catalytic inhibitors of topoisomerase II have been described, preclinical concepts for exploiting their anti-proliferative activity based on molecular characteristics of the tumor cell have only recently started to emerge. Topoisomerase II is an ATPase and uses the energy derived from ATP hydrolysis to orchestrate the movement of the DNA double strands along the enzyme. Thus, interfering with ATPase function with low molecular weight inhibitors that target the nucleotide binding pocket should profoundly affect cells that are committed to undergo mitosis. Here we describe the discovery and characterization of a novel purine diamine analogue as a potent ATP-competitive catalytic inhibitor of topoisomerase II. Quinoline aminopurine compound 1 (QAP 1) inhibited topoisomerase II ATPase activity and decatenation reaction at sub-micromolar concentrations, targeted both topoisomerase II alpha and beta in cell free assays and, using a quantitative cell-based assay and a chromosome segregation assay, displayed catalyt...Continue Reading

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Methods Mentioned

BETA
Assay
pull down
FACS
immunoprecipitation
PCR
electrophoresis
transfect
transfection
fluorescence microscopy

Software Mentioned

XLfit
SoftMax Pro
Adobe Photoshop
analySIS
Grafit
Odyssey
Macromodel
Erithacus

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