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

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

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.

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Benzamides / therapeutic use*
  • Cytokines / immunology
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Drug Repositioning
  • Endotoxemia / drug therapy*
  • Endotoxemia / immunology
  • Escherichia coli Infections / drug therapy*
  • Escherichia coli Infections / immunology
  • Female
  • Lipopolysaccharides / pharmacology
  • Mice, Inbred C57BL
  • NF-KappaB Inhibitor alpha / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Sepsis / drug therapy*
  • Sepsis / immunology
  • Transcriptome / drug effects

Substances

  • Benzamides
  • Cytokines
  • Lipopolysaccharides
  • Protein Kinase Inhibitors
  • Pyrimidines
  • NF-KappaB Inhibitor alpha
  • N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt