Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-[kappa]B 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[gamma] 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 [alpha] (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.