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

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.
Author summary Aberrant up-regulation of the transcription factor nuclear factor κB (NF-κB) and the IκB kinase (IKK) that regulates NF-κB is associated with a variety of inflammatory and degenerative diseases in humans, including aging. Thus, development of effective and specific drugs able to decrease IKK/NF-κB activity has significant therapeutic potential. In this study, a structure-derived computational approach was used to screen for small-molecule inhibitors of the protein–protein interaction between the IKKß and IKKγ subunits of the IKK complex. We identified and developed a novel class of small molecules that selectively inhibit IKK/NF-κB activation by dissociating the IKK complex without affecting c-Jun N-terminal kinase (JNK)/p38-mitogen-activated protein kinase (MAPK) signaling. These novel molecules reduce lipopolysaccharide (LPS)-induced acute inflammation in mice and improve muscle pathology in the mdx mouse model of Duchenne muscular dystrophy (DMD), suggesting that they would have potential clinical utility.