Discovery of new ATP-competitive inhibitors of human DNA topoisomerase IIα through screening of bacterial topoisomerase inhibitors.
ATP-competitive inhibitor
Anticancer drug
Biological screening
DNA topoisomerase II
N-phenylpyrrolamide
Journal
Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
12
04
2020
revised:
19
06
2020
accepted:
25
06
2020
pubmed:
21
7
2020
medline:
9
3
2021
entrez:
21
7
2020
Statut:
ppublish
Résumé
Human DNA topoisomerase II is one of the major targets in anticancer therapy, however ATP-competitive inhibitors of this target have not yet reached their full potential. ATPase domain of human DNA topoisomerase II belongs to the GHKL ATPase superfamily and shares a very high 3D structural similarity with other superfamily members, including bacterial topoisomerases. In this work we report the discovery of a new chemotype of ATP-competitive inhibitors of human DNA topoisomerase IIα that were discovered through screening of in-house library of ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV. Systematic screening of this library provided us with 20 hit compounds. 1,2,4-Substituted N-phenylpyrrolamides were selected for a further exploration which resulted in 13 new analogues, including 52 with potent activity in relaxation assay (IC
Identifiants
pubmed: 32688116
pii: S0045-2068(20)31346-8
doi: 10.1016/j.bioorg.2020.104049
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Topoisomerase II Inhibitors
0
Adenosine Triphosphatases
EC 3.6.1.-
DNA Topoisomerases, Type II
EC 5.99.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104049Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.