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

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

2018

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.

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