Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 10, Pages 7334-7362Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00356?
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Funding
- Natural Science Foundation of China [21977001, 2020xkjT008]
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Increasing IL-10 levels through CDK8 inhibition is a promising strategy for suppressing inflammatory diseases like IBD. This study describes the discovery of a novel CDK8 inhibitor (compound85) that effectively upregulates IL-10 both in vitro and in vivo, and exhibits potent anti-inflammatory activity in an animal model of IBD.
: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
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