Drug Repurposing of Histone Deacetylase Inhibitors That Alleviate Neutrophilic Inflammation in Acute Lung Injury and Idiopathic Pulmonary Fibrosis via Inhibiting Leukotriene A4 Hydrolase and Blocking LTB4 Biosynthesis.
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| Abstract |
Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, we identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide (2), are effective inhibitors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4), across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Importantly, both 1 and 2 markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose. Detailed mechanisms of down-regulation of proinflammatory cytokines by 1 or 2 were determined in vivo. Collectively, 1 and 2 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
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| Authors | Weiqiang Lu, Xue Yao, Ping Ouyang, Ningning Dong, Dang Wu, Xingwu Jiang, Zengrui Wu, Chen Zhang, Zhongyu Xu, Yun Tang, Shien Zou, Mingyao Liu, Jian Li, Minghua Zeng, Ping Lin, Feixiong Cheng, Jin Huang |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 5 Pg. 1817-1828 (03 09 2017) ISSN: 1520-4804 [Electronic] United States |
| PMID | 28218840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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