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Drug repositioning of TANK-binding kinase 1 inhibitor CYT387 as an alternative for the treatment of Gram-negative bacterial sepsis.
Int Immunopharmacol 2019; 73:482-490II

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.

Authors+Show Affiliations

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.Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea.Department of Biochemistry, School of Medicine, Konkuk University, Seoul, South Korea.Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea.Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University, Chungju 380-701, South Korea.Department of Biochemistry, School of Medicine, Konkuk University, Seoul, South Korea.Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.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.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31173970

Citation

Lee, Seung Jun, et al. "Drug Repositioning of TANK-binding Kinase 1 Inhibitor CYT387 as an Alternative for the Treatment of Gram-negative Bacterial Sepsis." International Immunopharmacology, vol. 73, 2019, pp. 482-490.
Lee SJ, Gharbi A, You JS, et al. Drug repositioning of TANK-binding kinase 1 inhibitor CYT387 as an alternative for the treatment of Gram-negative bacterial sepsis. Int Immunopharmacol. 2019;73:482-490.
Lee, S. J., Gharbi, A., You, J. S., Han, H. D., Kang, T. H., Hong, S. H., ... Park, Y. M. (2019). Drug repositioning of TANK-binding kinase 1 inhibitor CYT387 as an alternative for the treatment of Gram-negative bacterial sepsis. International Immunopharmacology, 73, pp. 482-490. doi:10.1016/j.intimp.2019.05.051.
Lee SJ, et al. Drug Repositioning of TANK-binding Kinase 1 Inhibitor CYT387 as an Alternative for the Treatment of Gram-negative Bacterial Sepsis. Int Immunopharmacol. 2019;73:482-490. PubMed PMID: 31173970.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drug repositioning of TANK-binding kinase 1 inhibitor CYT387 as an alternative for the treatment of Gram-negative bacterial sepsis. AU - Lee,Seung Jun, AU - Gharbi,Amal, AU - You,Jueng Soo, AU - Han,Hee Dong, AU - Kang,Tae Heung, AU - Hong,Seong Hwi, AU - Park,Won Sun, AU - Jung,In Duk, AU - Park,Yeong-Min, Y1 - 2019/06/04/ PY - 2019/03/11/received PY - 2019/05/27/revised PY - 2019/05/27/accepted PY - 2019/6/8/pubmed PY - 2019/6/8/medline PY - 2019/6/8/entrez KW - CYT387 KW - Drug repositioning KW - Endotoxemia KW - Infection KW - Inflammation KW - Sepsis KW - Tbk1 SP - 482 EP - 490 JF - International immunopharmacology JO - Int. Immunopharmacol. VL - 73 N2 - 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. SN - 1878-1705 UR - https://www.unboundmedicine.com/medline/citation/31173970/Drug_repositioning_of_TANK-binding_kinase_1_inhibitor_CYT387_as_an_alternative_for_the_treatment_of_Gram-negative_bacterial_sepsis L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-5769(19)30518-1 DB - PRIME DP - Unbound Medicine ER -