2. Academic Validation
  3. A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation

A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation

  • Nat Chem Biol. 2014 Dec;10(12):1055-60. doi: 10.1038/nchembio.1669.
Sanghee Lee 1,  Youngpyo Nam 2,  Ja Young Koo 1,  Donghyun Lim 3,  Jongmin Park 1,  Jiyeon Ock 2,  Jaehong Kim 2,  Kyoungho Suk 2,  Seung Bum Park 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Seoul National University, Seoul, Korea.
  • 2 Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
  • 3 Department of Biophysics and Chemical Biology/N-Bio Institute, Seoul National University, Seoul, Korea.
  • 4 1] Department of Chemistry, Seoul National University, Seoul, Korea. [2] Department of Biophysics and Chemical Biology/N-Bio Institute, Seoul National University, Seoul, Korea.
PMID: 25306442 DOI: 10.1038/nchembio.1669
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.

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