Discovery of a new class of catalytic topoisomerase II inhibitors targeting the ATP-binding site by structure based design. Part I.
Topoisomerase II is a validated target in oncology. Among the different ways of blocking the function of this enzyme, inhibiting its ATPase activity has been relatively less investigated. In an effort to identify topoisomerase II inhibitors of a novel type, exerting their action by this mechanism, we have designed a purine inhibitor scaffold targeting the ATP-binding site of the enzyme. Searching the Novartis compound collection for molecules containing this purine motif has allowed the identification of two micromolar hits providing access to a new class of catalytic topoisomerase II inhibitors.
Furet
Pascal
P
Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland. pascal.furet@novartis.com
Schoepfer
Joseph
J
Radimerski
Thomas
T
Chène
Patrick
P
D000255:Adenosine Triphosphate / Q000737:chemistry*; D020816:Amino Acid Motifs; D001665:Binding Sites; D002384:Catalysis; D002626:Chemistry, Pharmaceutical / Q000379:methods; D019295:Computational Biology / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011687:Purines / Q000737:chemistry; D059005:Topoisomerase II Inhibitors
D004791:Enzyme Inhibitors; D011687:Purines; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate