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.
Highlights
Nuclear factor κB (NF-κB) is a transcription factor essential for regulating immune responses, cell proliferation, apoptosis, embryonic development, senescence, and cancer [1]
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
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 Nterminal kinase (JNK)/p38-mitogen-activated protein kinase (MAPK) signaling
Summary
Nuclear factor κB (NF-κB) is a transcription factor essential for regulating immune responses, cell proliferation, apoptosis, embryonic development, senescence, and cancer [1]. The NF-κB family is composed of 5 subunits, RelA/p65, RelB, C-Rel, p50 (p105/NFκB1), and p52 (p100/NF-κB2), all containing a Rel-homology domain (RHD) required for homo- or heterodimerization [1]. NF-κB dimers are sequestered in the cytoplasm by an inhibitory protein IκBα, which masks the conserved nuclear localization sequence (NLS) of RelA/ p65 to prevent nuclear translocation [1]. IκBα undergoes phosphorylation, polyubiquitination, and proteasome-mediated degradation, releasing the NF-κB dimers to enable nuclear translocation [1]. This activated NF-κB down- or up-regulates target gene expression by binding to the κB enhancer or promoter elements [1]. Inducers of NF-κB activity include pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL-1), and lipopolysaccharide (LPS), as well as T-cell receptor (TCR) ligands, genotoxic, and oxidative stress [1]
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