Discovery and Anti-Inflammatory Activity Evaluation of a NovelCDK8 Inhibitor through Upregulation of IL-10 for the Treatment ofInflammatory Bowel DiseaseIn Vivo

摘要

:increasing the anti-inflammatory cytokine interleukin-10(IL-10) level is a promising strategy to suppress the progression ofpathogenic inflammation including inflammatory bowel disease (IBD).Since cyclin-dependent kinase 8 (CDK8) inhibition can upregulate IL-10abundance in activated myeloid-derived dendritic cells, it is considered tobe an effective target for IBD treatment. Here, the complete discoveryprocess of a novel CDK8 inhibitor as an anti-inflammatory agent wasdescribed. Starting with wogonin, structure-based optimization andstructure-activity relationship (SAR) study were comprehensively carriedout, and then lead compound85(N-(2-ethylphenyl)-5-(4-(piperazine-1-carbonyl)phenyl)nicotinamide) was developed as a potent druglike CDK8inhibitor upregulating IL-10 bothin vivoandin vitro. Also, compound85(with CDK8 IC50= 56 nM, IL-10 enhancement rate 88) exhibitedeffective anti-inflammatory activity in an animal model of IBD. These results confirmed that certain CDK8 inhibitor could be used asan effective anti-IBD drug