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Int Immunopharmacol. 2019 Aug;73:482-490. doi: 10.1016/j.intimp.2019.05.051. Epub 2019 Jun 4.

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

Author information

1
Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea; Department of Infection Control Science, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
2
Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea.
3
Department of Biochemistry, School of Medicine, Konkuk University, Seoul, South Korea.
4
Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.
5
Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea. Electronic address: jungid@kku.ac.kr.
6
Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea. Electronic address: immun3023@kku.ac.kr.

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.

KEYWORDS:

CYT387; Drug repositioning; Endotoxemia; Infection; Inflammation; Sepsis; Tbk1

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