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

Sanghee Lee; Youngpyo Nam; Ja Y.oung Koo; Donghyun Lim; Jongmin Park; Jiyeon Ock; Jaehong Kim; Kyoungho Suk; Seung B.um Park

doi:10.1038/nchembio.1669

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

Sanghee Lee, Youngpyo Nam, Ja Y.oung Koo, Donghyun Lim, Jongmin Park, Jiyeon Ock, Jaehong Kim, Kyoungho Suk, Seung B.um Park

Department of Medicine

Kyungpook National University

Research output: Contribution to journal › Article › peer-review

98 Scopus citations

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.

Original language	English
Pages (from-to)	1055-1060
Number of pages	6
Journal	Nature Chemical Biology
Volume	10
Issue number	12
DOIs	https://doi.org/10.1038/nchembio.1669
State	Published - 1 Dec 2014

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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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AU - Park, Jongmin

AU - Ock, Jiyeon

AU - Kim, Jaehong

AU - Suk, Kyoungho

AU - Park, Seung B.um

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

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