title: A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation.
abstract: Because of the critical role of neuroinflammation in various neurological diseases, there are continuous efforts to identify new therapeutic targets as well as new therapeutic agents to treat neuroinflammatory diseases. Here we report the discovery of inflachromene (ICM), a microglial inhibitor with anti-inflammatory effects. Using the convergent strategy of phenotypic screening with early stage target identification, we show that the direct binding target of ICM is the high mobility group box (HMGB) proteins. Mode-of-action studies demonstrate that ICM blocks the sequential processes of cytoplasmic localization and extracellular release of HMGBs by perturbing its post-translational modification. In addition, ICM effectively downregulates proinflammatory functions of HMGB and reduces neuronal damage in vivo. Our study reveals that ICM suppresses microglia-mediated inflammation and exerts a neuroprotective effect, demonstrating the therapeutic potential of ICM in neuroinflammatory diseases.
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, Korea.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Youngpyo
authors.initials: Y
authors.lastname: Nam
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, Korea.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Koo
authors.affiliation: Department of Biophysics and Chemical Biology/N-Bio Institute, Seoul National University, Seoul, Korea.
authors.forename: Donghyun
authors.initials: D
authors.lastname: Lim
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, Korea.
authors.forename: Jongmin
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Ock
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Jaehong
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
authors.affiliation: 1] Department of Chemistry, Seoul National University, Seoul, Korea. [2] Department of Biophysics and Chemical Biology/N-Bio Institute, Seoul National University, Seoul, Korea.
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D018920:Coculture Techniques; D015870:Gene Expression; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D024261:HMGB2 Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D015213:Neuroimmunomodulation; D009474:Neurons / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D024261:HMGB2 Protein; D006576:Heterocyclic Compounds, 4 or More Rings; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; C000594653:inflachromene