title: 4,6-Substituted-1,3,5-triazin-2(1H)-ones as monocyclic catalytic inhibitors of human DNA topoisomerase IIα targeting the ATP binding site.
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.
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pogorelčnik
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
authors.forename: Matej
authors.initials: M
authors.lastname: Janežič
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
authors.forename: Tom
authors.initials: T
authors.lastname: Solmajer
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia. Electronic address: andrej.perdih@ki.si.
authors.forename: Andrej
authors.initials: A
authors.lastname: Perdih
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014227:Triazines
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D054852:Small Molecule Libraries; D059005:Topoisomerase II Inhibitors; D014227:Triazines; D005047:Etoposide; D000255:Adenosine Triphosphate; D004250:DNA Topoisomerases, Type II
keywords: ATPase assay; Catalytic inhibitors; Cleavage assay; Computer-aided drug design; Decatenation assay; Human DNA topoisomerase IIα; Microscale thermophoresis (MST)