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

  • PLoS Biol. 2018 Jun 11;16(6):e2004663. doi: 10.1371/journal.pbio.2004663.
Jing Zhao  1  2 ,  Lei Zhang  1 ,  Xiaodong Mu  3 ,  Christelle Doebelin  1 ,  William Nguyen  1 ,  Callen Wallace  4 ,  Daniel P Reay  5 ,  Sara J McGowan  1 ,  Lana Corbo  1 ,  Paula R Clemens  5 ,  Gabriela Mustata Wilson  6 ,  Simon C Watkins  4 ,  Laura A Solt  7 ,  Michael D Cameron  1 ,  Johnny Huard  3 ,  Laura J Niedernhofer  1 ,  Theodore M Kamenecka  1 ,  Paul D Robbins  1
Affiliations
  • 1. Department of Molecular Medicine and the TSRI Center on Aging, The Scripps Research Institute, Jupiter, Florida, United States of America.
  • 2. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
  • 3. Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
  • 4. Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
  • 5. Department of Neurology, University of Pittsburgh, Pennsylvania, United States of America.
  • 6. Department of Health Informatics and Information Management, College of Nursing and Health Professions, University of Southern Indiana, Evansville, Indiana, United States of America.
  • 7. Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, United States of America.
PMID: 29889904 DOI: 10.1371/journal.pbio.2004663
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.

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