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

Nature Chemical Biology volume 10, pages 1055–1060 (2014)Cite this article

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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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Figure 1: Discovery of ICM as an anti-inflammatory agent in LPS-induced microglial activation.
Figure 2: Target identification of ICM by 1D and 2D gel analysis in live cells.
Figure 3: Functional validation of HMGB2 as a direct binding target of ICM.
Figure 4: Mode-of-action study of ICM for perturbing the inflammatory function of HMGB2.
Figure 5: The therapeutic effect of ICM in vivo.

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Acknowledgements

This work was supported by a Creative Research Initiative grant (2014R1A3A2030423), the Bio & Medical Technology Development Program (2012M3A9C4048780) and the Basic Research Laboratory (2010-0019766) funded by the National Research Foundation of Korea (NRF). K.S. was supported by a NRF grant funded by the Korean government (MSIP) (2008-0062282) and a grant of the Korea Healthcare Technology R&D Project, Korean Ministry of Health and Welfare (A111345). S.L., Y.N., J.Y.K., D.L., J.P. and J.K. are grateful for a BK21 Scholarship.

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Authors and Affiliations

  1. Department of Chemistry, Seoul National University, Seoul, Korea

    Sanghee Lee, Ja Young Koo, Jongmin Park & Seung Bum Park

  2. Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea

    Youngpyo Nam, Jiyeon Ock, Jaehong Kim & Kyoungho Suk

  3. Department of Biophysics and Chemical Biology/N-Bio Institute, Seoul National University, Seoul, Korea

    Donghyun Lim & Seung Bum Park

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  1. Sanghee Lee
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Contributions

S.L. performed the biochemical assays, analyzed the data and prepared the manuscript. Y.N. and J.K. performed the biochemical assays and in vivo experiments and analyzed the data. J.Y.K. synthesized the compounds and conducted the computational study. D.L. and J.O. performed experiments for target validation. J.P. contributed to the target identification. K.S. and S.B.P. directed the study and were involved in all aspects of the experimental design, data analysis and manuscript preparation. All authors critically reviewed the text and figures.

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Correspondence to Kyoungho Suk or Seung Bum Park.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Figures 1–30, Supplementary Note and Supplementary Tables 1–5. (PDF 7939 kb)

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Lee, S., Nam, Y., Koo, J. et al. A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation. Nat Chem Biol 10, 1055–1060 (2014). https://doi.org/10.1038/nchembio.1669

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