title: Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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 catalytic enzyme inhibition in cells. In agreement with recent hypothesis, we show that BRCA1 mutant breast cancer cells have increased sensitivity to QAP 1.
  
  
  CONCLUSIONS
  The results obtained with QAP 1 demonstrate that potent and selective catalytic inhibition of human topoisomerase II function with an ATP-competitive inhibitor is feasible. Our data suggest that further drug discovery efforts on ATP-competitive catalytic inhibitors are warranted and that such drugs could potentially be developed as anti-cancer therapy for tumors that bear the appropriate combination of molecular alterations.
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chène
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Rudloff
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schoepfer
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Meier
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Biologics Center, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Schlaeppi
authors.affiliation: Biologics Center, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Rita
authors.initials: R
authors.lastname: Schmitz
authors.affiliation: Department of Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski