Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation

Jing Zhao, Lei Zhang, Xiaodong Mu, Christelle Doebelin, William Nguyen, Callen Wallace, Daniel P. Reay, Sara J. McGowan, Lana Corbo, Paula R. Clemens, Gabriela Mustata Wilson, Simon C. Watkins, Laura A. Solt, Michael D. Cameron, Johnny Huard, Laura J. Niedernhofer, Theodore M. Kamenecka, Paul D. Robbins

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7 Scopus citations

Abstract

Nuclear factor κB (NF-κB) is a transcription factor important for regulating innate and adaptive immunity, cellular proliferation, apoptosis, and senescence. Dysregulation of NF-κB and its upstream regulator IκB kinase (IKK) contributes to the pathogenesis of multiple inflammatory and degenerative diseases as well as cancer. An 11–amino acid peptide containing the NF-κB essential modulator (NEMO)-binding domain (NBD) derived from the C-terminus of β subunit of IKK, functions as a highly selective inhibitor of the IKK complex by disrupting the association of IKKβ and the IKKγ subunit NEMO. A structure-based pharmacophore model was developed to identify NBD mimetics by in silico screening. Two optimized lead NBD mimetics, SR12343 and SR12460, inhibited tumor necrosis factor α (TNF-α)- and lipopolysaccharide (LPS)-induced NF-κB activation by blocking the interaction between IKKβ and NEMO and suppressed LPS-induced acute pulmonary inflammation in mice. Chronic treatment of a mouse model of Duchenne muscular dystrophy (DMD) with SR12343 and SR12460 attenuated inflammatory infiltration, necrosis and muscle degeneration, demonstrating that these small-molecule NBD mimetics are potential therapeutics for inflammatory and degenerative diseases.

Original languageEnglish (US)
Article numbere2004663
JournalPLoS biology
Volume16
Issue number6
DOIs
StatePublished - Jun 2018

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    Zhao, J., Zhang, L., Mu, X., Doebelin, C., Nguyen, W., Wallace, C., Reay, D. P., McGowan, S. J., Corbo, L., Clemens, P. R., Wilson, G. M., Watkins, S. C., Solt, L. A., Cameron, M. D., Huard, J., Niedernhofer, L. J., Kamenecka, T. M., & Robbins, P. D. (2018). Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation. PLoS biology, 16(6), [e2004663]. https://doi.org/10.1371/journal.pbio.2004663