Hit Identification of IKKβ Natural Product Inhibitor

Overview

Journal BMC Pharmacol Toxicol

Publisher Biomed Central

Specialty Pharmacology

Date 2013 Jan 9

PMID 23294515

Citations 6

Authors

Chung-Hang Leung

Daniel Shiu-Hin Chan

Ying-Wei Li

Wang-Fun Fong

Dik-Lung Ma

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Citing Articles

approaches for drug repurposing in oncology: a scoping review.

Cavalcante B, Freitas R, Siquara da Rocha L, Santos R, Souza B, Ramos P Front Pharmacol. 2024; 15:1400029.

PMID: 38919258 PMC: 11196849. DOI: 10.3389/fphar.2024.1400029.

Evaluation of the IKKβ Binding of Indicaxanthin by Induced-Fit Docking, Binding Pose Metadynamics, and Molecular Dynamics.

Allegra M, Tutone M, Tesoriere L, Attanzio A, Culletta G, Almerico A Front Pharmacol. 2021; 12:701568.

PMID: 34566634 PMC: 8461089. DOI: 10.3389/fphar.2021.701568.

Protective effects and mechanism of coenzyme Q10 and vitamin C on doxorubicin-induced gastric mucosal injury and effects of intestinal flora.

Zhao X, Feng X, Ye N, Wei P, Zhang Z, Lu W Korean J Physiol Pharmacol. 2021; 25(4):261-272.

PMID: 34187945 PMC: 8255120. DOI: 10.4196/kjpp.2021.25.4.261.

An innovative cell model revealed the inhibitory effect of flavanone structure on peroxynitrite production through interaction with the IKKβ kinase domain at ATP binding site.

Charoensin S, Huang T, Hsu J Food Sci Nutr. 2020; 8(6):2904-2912.

PMID: 32566208 PMC: 7300029. DOI: 10.1002/fsn3.1591.

Design, synthesis, and biological evaluation of novel and analogs as potential IκB kinase β inhibitors for the treatment of pancreatic cancer.

Xie X, Tu J, You H, Hu B Drug Des Devel Ther. 2017; 11:1439-1451.

PMID: 28553074 PMC: 5440027. DOI: 10.2147/DDDT.S133172.

References

Zhong H, Ma V, Cheng Z, Chan D, He H, Leung K . Discovery of a natural product inhibitor targeting protein neddylation by structure-based virtual screening. Biochimie. 2012; 94(11):2457-60. DOI: 10.1016/j.biochi.2012.06.004. View

Ma D, Lai T, Chan F, Chung W, Abagyan R, Leung Y . Discovery of a drug-like G-quadruplex binding ligand by high-throughput docking. ChemMedChem. 2008; 3(6):881-4. DOI: 10.1002/cmdc.200700342. View

Kempson J, Spergel S, Guo J, Quesnelle C, Gill P, Belanger D . Novel tricyclic inhibitors of IkappaB kinase. J Med Chem. 2009; 52(7):1994-2005. DOI: 10.1021/jm8015816. View

Karin M . How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex. Oncogene. 1999; 18(49):6867-74. DOI: 10.1038/sj.onc.1203219. View

Ma D, Ma V, Chan D, Leung K, Zhong H, Leung C . In silico screening of quadruplex-binding ligands. Methods. 2012; 57(1):106-14. DOI: 10.1016/j.ymeth.2012.02.001. View

Karin M, Cao Y, Greten F, Li Z . NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002; 2(4):301-10. DOI: 10.1038/nrc780. View

Karin M, Yamamoto Y, Wang Q . The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov. 2004; 3(1):17-26. DOI: 10.1038/nrd1279. View

Ghose A, Herbertz T, Pippin D, Salvino J, Mallamo J . Knowledge based prediction of ligand binding modes and rational inhibitor design for kinase drug discovery. J Med Chem. 2008; 51(17):5149-71. DOI: 10.1021/jm800475y. View

Bajorath J . Integration of virtual and high-throughput screening. Nat Rev Drug Discov. 2002; 1(11):882-94. DOI: 10.1038/nrd941. View

10.

Chan D, Yang H, Kwan M, Cheng Z, Lee P, Bai L . Structure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer. Biochimie. 2011; 93(6):1055-64. DOI: 10.1016/j.biochi.2011.02.013. View

11.

Karin M, Ben-Neriah Y . Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000; 18:621-63. DOI: 10.1146/annurev.immunol.18.1.621. View

12.

Ma D, Chan D, Leung C . Drug repositioning by structure-based virtual screening. Chem Soc Rev. 2013; 42(5):2130-41. DOI: 10.1039/c2cs35357a. View

13.

Crombie A, Sum F, Powell D, Hopper D, Torres N, Berger D . Synthesis and biological evaluation of tricyclic anilinopyrimidines as IKKbeta inhibitors. Bioorg Med Chem Lett. 2010; 20(12):3821-5. DOI: 10.1016/j.bmcl.2010.04.022. View

14.

Kempson J, Guo J, Das J, Moquin R, Spergel S, Watterson S . Synthesis, initial SAR and biological evaluation of 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine derived inhibitors of IkappaB kinase. Bioorg Med Chem Lett. 2009; 19(10):2646-9. DOI: 10.1016/j.bmcl.2009.03.159. View

15.

Cowan-Jacob S, Fendrich G, Manley P, Jahnke W, Fabbro D, Liebetanz J . The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation. Structure. 2005; 13(6):861-71. DOI: 10.1016/j.str.2005.03.012. View

16.

Schmid J, Birbach A . IkappaB kinase beta (IKKbeta/IKK2/IKBKB)--a key molecule in signaling to the transcription factor NF-kappaB. Cytokine Growth Factor Rev. 2008; 19(2):157-65. DOI: 10.1016/j.cytogfr.2008.01.006. View

17.

Chan D, Lee H, Yang F, Che C, Wong C, Abagyan R . Structure-based discovery of natural-product-like TNF-α inhibitors. Angew Chem Int Ed Engl. 2010; 49(16):2860-4. PMC: 4162403. DOI: 10.1002/anie.200907360. View

18.

Breinbauer R, Vetter I, Waldmann H . From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem Int Ed Engl. 2002; 41(16):2879-90. DOI: 10.1002/1521-3773(20020816)41:16<2878::AID-ANIE2878>3.0.CO;2-B. View

19.

Christopher J, Bamborough P, Alder C, Campbell A, Cutler G, Down K . Discovery of 6-aryl-7-alkoxyisoquinoline inhibitors of IkappaB kinase-beta (IKK-beta). J Med Chem. 2009; 52(9):3098-102. DOI: 10.1021/jm9000117. View

20.

Gilmore T . Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 2006; 25(51):6680-4. DOI: 10.1038/sj.onc.1209954. View