Pogorelčnik Barbara, Janežič Matej, Sosič Izidor, Gobec Stanislav, Solmajer Tom, Perdih Andrej
National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Bioorg Med Chem. 2015 Aug 1;23(15):4218-4229. doi: 10.1016/j.bmc.2015.06.049. Epub 2015 Jul 2.
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.
人类DNA拓扑异构酶IIα（htIIα）是新型抗癌药物开发的一个经过验证的靶点。从我们发现的htIIα的4-氨基-1,3,5-三嗪抑制剂出发，我们使用基于结构和基于配体的药效团模型以及分子对接相结合的方法，研究了一个2,4,6-三取代-1,3,5-三嗪文库，以寻找与htIIα ATP结合位点结合的新型抑制剂。4,6-取代-1,3,5-三嗪-2(1H)-酮8、9和14被鉴定为新型抑制剂，其活性与已上市药物依托泊苷（1）相当。化合物8抑制htIIα解连环的能力优于依托泊苷。切割试验表明，所选化合物8和14不是毒物，并且拮抗依托泊苷的毒性作用。微量热泳动（MST）证实化合物8与htIIα ATP酶结构域结合，化合物14有效抑制htIIα介导的ATP水解。分子动力学模拟研究进一步深入了解了分子识别过程。4,6-二取代-1,3,5-三嗪-2(1H)-酮代表了首个经过验证的与htIIα ATP酶结构域结合的单环类催化抑制剂。
