Hit identification of IKKβ natural product inhibitor
Leung C.-H.2; Chan D.S.H.1; Li Y.-W.1; Fong W.-F.1; Ma D.-L.1
Source PublicationBMC Pharmacology and Toxicology
AbstractBackground: The nuclear factor-κB (NF-κB) proteins are a small group of heterodimeric transcription factors that play an important role in regulating the inflammatory, immune, and apoptotic responses. NF-κB activity is suppressed by association with the inhibitor IκB. Aberrant NF-κB signaling activity has been associated with the development of cancer, chronic inflammatory diseases and auto-immune diseases. The IKK protein complex is comprised of IKKα, IKKβ and NEMO subunits, with IKKβ thought to play the dominant role in modulating NF-κB activity. Therefore, the discovery of new IKKβ inhibitors may offer new therapeutic options for the treatment of cancer and inflammatory diseases.Results: A structure-based molecular docking approach has been employed to discover novel IKKβ inhibitors from a natural product library of over 90,000 compounds. Preliminary screening of the 12 highest-scoring compounds using a luciferase reporter assay identified 4 promising candidates for further biological study. Among these, the benzoic acid derivative (1) showed the most promising activity at inhibiting IKKβ phosphorylation and TNF-α-induced NF-κB signaling in vitro.Conclusions: In this study, we have successfully identified a benzoic acid derivative (1) as a novel IKKβ inhibitor via high-throughput molecular docking. Compound 1 was able to inhibit IKKβ phosphorylation activity in vitro, and block IκBα protein degradation and subsequent NF-κB activation in human cells. Further in silico optimization of the compound is currently being conducted in order to generate more potent analogues for biological tests. © 2013 Leung et al.; licensee BioMed Central Ltd.
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Cited Times [WOS]:17   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Hong Kong Baptist University
2.University of Macau
First Author AffilicationUniversity of Macau
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GB/T 7714
Leung C.-H.,Chan D.S.H.,Li Y.-W.,et al. Hit identification of IKKβ natural product inhibitor[J]. BMC Pharmacology and Toxicology,2013,14.
APA Leung C.-H.,Chan D.S.H.,Li Y.-W.,Fong W.-F.,&Ma D.-L..(2013).Hit identification of IKKβ natural product inhibitor.BMC Pharmacology and Toxicology,14.
MLA Leung C.-H.,et al."Hit identification of IKKβ natural product inhibitor".BMC Pharmacology and Toxicology 14(2013).
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