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.核因子κB（Nuclear factor κB，NF-κB）是一类关键转录因子，在调控固有免疫与适应性免疫、细胞增殖、细胞凋亡及细胞衰老过程中发挥重要作用。核因子κB及其上游调控因子IκB激酶（IκB kinase，IKK）的失调，与多种炎症性、退行性疾病及癌症的发病机制密切相关。源自IKK β亚基羧基端的、包含NF-κB必需调节蛋白（NEMO）结合结构域（NBD）的11氨基酸肽段，可通过破坏IKKβ与IKKγ亚基NEMO的相互作用，作为高选择性的IKK复合物抑制剂。研究人员构建了基于结构的药效团模型，通过计算机虚拟筛选识别NBD模拟物。两款经优化的先导NBD模拟物SR12343与SR12460，可通过阻断IKKβ与NEMO的相互作用，抑制肿瘤坏死因子α（TNF-α）及脂多糖（LPS）诱导的核因子κB活化，并在小鼠体内减轻LPS诱导的急性肺部炎症。在杜氏肌营养不良症（DMD）小鼠模型中，长期给予SR12343与SR12460可缓解炎性浸润、坏死及肌肉变性，证实这类小分子NBD模拟物有望成为炎症性与退行性疾病的潜在治疗药物。