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

Nuclear factor kappa B (NF-kappa B) is a transcription factor important for regulating innate and adaptive immunity, cellular proliferation, apoptosis, and senescence. Dysregulation of NF-kappa B and its upstream regulator I kappa B kinase (IKK) contributes to the pathogenesis of multiple inflammatory and degenerative diseases as well as cancer. An 11 +/- amino acid peptide containing the NF-kappa B essential modulator (NEMO)-binding domain (NBD) derived from the C-terminus of beta subunit of IKK, functions as a highly selective inhibitor of the IKK complex by disrupting the association of IKK beta and the IKK. 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 a (TNF-alpha)-and lipopolysaccharide (LPS)-induced NF-kappa B activation by blocking the interaction between IKK beta 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.