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J Med Chem. 2017 Mar 9;60(5):1817-1828. doi: 10.1021/acs.jmedchem.6b01507. Epub 2017 Feb 28.

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.

Author information

1
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
2
Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai 200241, China.
3
Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University , Shanghai 200011, China.
4
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education), School of Chemistry & Chemical Engineering, Guangxi Normal University , Guilin 541004, China.
5
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, Sichuan, China.
6
Center for Complex Networks Research, Northeastern University , Boston, Massachusetts 02115, United States.
7
Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School , Boston, Massachusetts 02215, United States.

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.

PMID:
28218840
DOI:
10.1021/acs.jmedchem.6b01507
[Indexed for MEDLINE]

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