Journal
BIOORGANIC CHEMISTRY
Volume 133, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2023.106402
Keywords
Interleukin 10; CDK8 inhibitor; Inflammatory bowel disease; Anti-inflammatory activity
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CDK8 inhibitor CR16 enhances the transcriptional activity of AP-1 and increases IL-10 abundance, showing potential therapeutic effect in IBD treatment.
As an ideal anti-inflammatory target, cyclin-dependent kinase 8 (CDK8) has gradually attracted the attention of researchers. CDK8 inhibition up-regulates Interleukin-10 (IL-10) expression by enhancing the transcriptional activity of activator protein-1 (AP-1), and augmenting IL-10 abundance is a viable strategy for the treatment of inflammatory bowel disease (IBD). In this research, through structure-based drug design and dominant fragment hybridization, a series of poly-substituted pyridine derivatives were designed and synthesized as CDK8 inhibitors. Ultimately, compound CR16 was identified as the best one, which exhibited good inhibitory activity against CDK8 (IC50 = 74.4 nM). In vitro and in vivo studies indicated that CR16 could enhance the transcriptional activity of AP-1, augment the abundance of IL-10, and affect CDK8-related signaling pathways including TLR7/NF-kappa B/ MAPK and IL-10-JAK1-STAT3 pathways. In addition, CR16 showed potent therapeutic effect in an animal model of IBD.
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