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Drug repositioning of TANK-binding kinase 1 inhibitor CYT387 as an alternative for the treatment of Gram-negative bacterial sepsis.

Abstract：

:There is currently no specific drug for the treatment of sepsis and antibiotic administration is considered the best option, despite numerous issues. Therefore, the development of drugs to control the pathogen-induced inflammatory responses associated with sepsis is essential. To address this, our study examined the transcriptomes of lipopolysaccharide (LPS)-induced dendritic cells (DCs), identifying TANK-binding kinase1 (Tbk1) as a key factor involved in the inflammatory response. These data suggested drug repositioning of the Tbk1 inhibitor CYT387, currently used for the treatment of myelofibrosis and some cancers, as a candidate for regulating the LPS-induced inflammatory response. CYT387 also inhibited pro-inflammatory cytokine and surface molecule expression by mature DCs after LPS exposure. These effects correlated with both Akt phosphorylation and IκBα degradation. Finally, CYT387 demonstrated therapeutic effects in LPS-induced endotoxemia and Escherichia coli K1-induced mouse models of sepsis and decreased the expression of pro-inflammatory cytokines. In conclusion, our study suggests that drug repositioning of CYT387 may serve as a potential therapeutic for sepsis.

journal_name

Int Immunopharmacol

journal_title

International immunopharmacology

authors

Lee SJ,Gharbi A,You JS,Han HD,Kang TH,Hong SH,Park WS,Jung ID,Park YM

doi

10.1016/j.intimp.2019.05.051

subject

Has Abstract

pub_date

2019-08-01 00:00:00

pages

482-490

eissn

1567-5769

issn

1878-1705

pii

S1567-5769(19)30518-1

journal_volume

73

pub_type

杂志文章

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