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DOI	10.1073/pnas.2016265118
	Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain
	Ahmed M.S.; Wang P.; Nhi Nguyen N.U.; Nakada Y.; Menendez-Montes I.; Ismail M.; Bachoo R.; Henkemeyer M.; Sadek H.A.; Kandil E.S.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Crystallography; Drug repurposing; EphB receptor; Neuropathic pain
语种	英语
scopus关键词	adenosine triphosphate; chlortetracycline; demeclocycline; ephrin receptor B1; minocycline; animal cell; animal experiment; animal model; animal tissue; Article; brain region; computer model; controlled study; crystallization; crystallography; drug receptor binding; drug repositioning; enzyme active site; enzyme activity; enzyme inhibition; enzyme phosphorylation; in vivo study; kinase assay; male; mouse; neuropathic pain; nonhuman; priority journal; spinal cord; spinal ganglion
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180426
作者单位	Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Pharmaceutical Chemistry, The British University in Egypt, Cairo, 11837, Egypt; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
推荐引用方式 GB/T 7714	Ahmed M.S.,Wang P.,Nhi Nguyen N.U.,et al. Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain[J],2021,118(10).
APA	Ahmed M.S..,Wang P..,Nhi Nguyen N.U..,Nakada Y..,Menendez-Montes I..,...&Kandil E.S..(2021).Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain.Proceedings of the National Academy of Sciences of the United States of America,118(10).
MLA	Ahmed M.S.,et al."Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain".Proceedings of the National Academy of Sciences of the United States of America 118.10(2021).