1. 4,6-Substituted-1,3,5-triazin-2(1H)-ones as monocyclic catalytic inhibitors of human DNA topoisomerase IIα targeting the ATP binding site.
- Author
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Pogorelčnik B, Janežič M, Sosič I, Gobec S, Solmajer T, and Perdih A
- Subjects
- Antigens, Neoplasm chemistry, Antigens, Neoplasm metabolism, Binding Sites, DNA Topoisomerases, Type II chemistry, DNA Topoisomerases, Type II metabolism, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins chemistry, DNA-Binding Proteins metabolism, Etoposide pharmacology, Humans, Molecular Docking Simulation, Molecular Structure, Protein Structure, Tertiary, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Topoisomerase II Inhibitors metabolism, Triazines, Adenosine Triphosphate metabolism, Drug Evaluation, Preclinical methods, Topoisomerase II Inhibitors chemistry, Topoisomerase II Inhibitors pharmacology
- Abstract
Human DNA topoisomerase IIα (htIIα) is a validated target for the development of novel anticancer agents. Starting from our discovered 4-amino-1,3,5-triazine inhibitors of htIIα, we investigated a library of 2,4,6-trisubstituted-1,3,5-triazines for novel inhibitors that bind to the htIIα ATP binding site using a combination of structure-based and ligand-based pharmacophore models and molecular docking. 4,6-substituted-1,3,5-triazin-2(1H)-ones 8, 9 and 14 were identified as novel inhibitors with activity comparable to the established drug etoposide (1). Compound 8 inhibits the htIIα decatenation in a superior fashion to etoposide. Cleavage assays demonstrated that selected compounds 8 and 14 do not act as poisons and antagonize the poison effect of etoposide. Microscale thermophoresis (MST) confirmed binding of compound 8 to the htIIα ATPase domain and compound 14 effectively inhibits the htIIα mediated ATP hydrolysis. The molecular dynamics simulation study provides further insight into the molecular recognition. The 4,6-disubstituted-1,3,5-triazin-2(1H)-ones represent the first validated monocyclic class of catalytic inhibitors that bind to the to the htIIα ATPase domain., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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