Discovery of new ATP-competitive inhibitors of human DNA topoisomerase IIα through screening of bacterial topoisomerase inhibitors

Skok, Žiga; Durcik, Martina; Skledar, Darja Gramec; Barančoková, Michaela; Mašič, Lucija Peterlin; Tomašič, Tihomir; Zega, Anamarija; Kikelj, D.; Zidar, Nace; Ilaš, Janez

doi:10.1016/j.bioorg.2020.104049

Cited by 10 publications

(4 citation statements)

References 51 publications

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“…The assay to determine IC 50 value for 7a was performed using assay kits from Inspiralis according to previously described procedures. 44 Seven concentrations of the inhibitors were used to determine IC 50 values which were then calculated with GraphPad Prism 6.0 software. Three independent measurements were performed to determine IC 50 values, and mean values are reported as the final result.…”

Section: Methodsmentioning

confidence: 99%

New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

et al. 2023

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A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis , Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125–0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1–4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.

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Section: Methodsmentioning

confidence: 99%

New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

et al. 2023

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“…Moreover, in Egypt, 2-(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbonyl)-N-(m-tolyl)-hydrazinecarbothioamide a derivative of nalidixic acid (14), has been shown to be a potent inhibitor of TopoIIα and TopoIIβ, and induced cell cycle arrest at G2-M phase leading to inhibition of cell proliferation and apoptosis [60]. According to Jiang et al [61], four compounds from a series of carbazole-rhodanine conjugates, was found possessing topoisomerase II inhibitory activity, with potency at 20 μM.…”

Section: -(4-(acridin-9ylamino)-phenyl)-1h-123-triazol-1-yl)-n-hydrox...mentioning

confidence: 99%

“…This study need further investigation as these compounds are phytochemicals and could be structural optimized to deliver efficient anticancer activity. Additionally, in Slovenia, Skok et al [14] used in silico screening of bacterial topoisomerase inhibitors with invitro assay to identify ATP-competitive inhibitors of human DNA TopoIIα, and they reported N-(4-Carbamoyl-2-isopropoxyphenyl)-3,4-dichloro-5-methyl-1Hpyrrole-2-carboxamide, as a potential active inhibitor of TopoIIα. Further investigation of these computationally screened compounds is necessary to validate their biological activity as anticancer agent.…”

Section: Introductionmentioning

confidence: 99%

A Mini Review of Novel Topoisomerase II Inhibitors as Future Anticancer Agents

Okoro¹,

Fatoki²

2022

Preprint

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Several reviews of inhibitors of topoisomerase II literature have been published covering research before 2018. Therefore, this review is focused primarily on more recent publications with relevant points from the earlier literature. Topoisomerase II is an established target for anticancer drugs, that are further subdivided into poisons and catalytic inhibitors. Whereas most of the topoisomerase II-based drugs in clinical use are mostly topoisomerase II poisons, their mechanism of action has posed severe concern due to DNA damaging potential, including development of multi drug resistance. As a result, we are beginning to see a gradual paradigm shift towards a non-DNA damaging agents, such as the lesser studied topoisomerase II catalytic inhibitors. In addition, this review will describe some novel selective catalytic topoisomerase II inhibitors. The ultimate goal is to bring researchers up to speed by curating and delineating new scaffolds as leads for optimization and development to new potent, safe and selective agents for the treatment of cancer.

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“…All of these Hsp90 inhibitors bind to the ATP-binding site at the NTD and not the allosteric site at the Hsp90 CTD that was identified for novobiocin. Furthermore, it has recently been shown that it is possible to convert GyrB inhibitors into Hsp90 [22][23][24][25] or TopoII [26] inhibitors by the introduction of small structural changes in the ligands. However, selectivity against TopoII and Hsp90 can be achieved by exploiting important differences between these enzymes involving amino acid residues in the ATP-binding sites (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Selective DNA Gyrase Inhibitors: Multi-Target in Silico Profiling with 3D-Pharmacophores

et al. 2021

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(1) Background: DNA gyrase is an important target for the development of novel antibiotics. Although ATP-competitive DNA gyrase (GyrB) inhibitors are a well-studied class of antibacterial agents, there is currently no representative used in therapy, largely due to unwanted off-target activities. Selectivity of GyrB inhibitors against closely related human ATP-binding enzymes should be evaluated early in development to avoid off-target binding to homologous binding domains. (2) Methods: To address this challenge, we developed selective 3D-pharmacophore models for GyrB, human topoisomerase IIα (TopoII), and the Hsp90 N-terminal domain (NTD) to be used in in silico activity profiling paradigms to identify molecules selective for GyrB over TopoII and Hsp90, as starting points for hit expansion and lead optimization. (3) Results: The models were used to profile highly active GyrB, TopoII, and Hsp90 inhibitors. Selected compounds were tested in in vitro assays. GyrB inhibitors 1 and 2 were inactive against TopoII and Hsp90, while 3 and 4, potent Hsp90 inhibitors, displayed no inhibition of GyrB and TopoII, and TopoII inhibitors 5 and 6 were inactive at GyrB and Hsp90. (4) Conclusions: The results provide a proof of concept for the use of target activity profiling methods to identify selective starting points for hit and lead identification.

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Discovery of new ATP-competitive inhibitors of human DNA topoisomerase IIα through screening of bacterial topoisomerase inhibitors

Cited by 10 publications

References 51 publications

New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

New Dual Inhibitors of Bacterial Topoisomerases with Broad-Spectrum Antibacterial Activity and In Vivo Efficacy against Vancomycin-Intermediate Staphylococcus aureus

A Mini Review of Novel Topoisomerase II Inhibitors as Future Anticancer Agents

Selective DNA Gyrase Inhibitors: Multi-Target in Silico Profiling with 3D-Pharmacophores

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