A novel CDK8 inhibitor with poly-substituted pyridine core: Discovery and anti-inflammatory activity evaluation in vivo

Bioorg Chem. 2023 Apr:133:106402. doi: 10.1016/j.bioorg.2023.106402. Epub 2023 Feb 10.

Abstract

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-κB/MAPK and IL-10-JAK1-STAT3 pathways. In addition, CR16 showed potent therapeutic effect in an animal model of IBD.

Keywords: Anti-inflammatory activity; CDK8 inhibitor; Inflammatory bowel disease; Interleukin 10.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase 8 / antagonists & inhibitors
  • Interleukin-10* / metabolism
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Pyridines / pharmacology
  • Signal Transduction
  • Transcription Factor AP-1

Substances

  • Cyclin-Dependent Kinase 8
  • Interleukin-10
  • Protein Kinase Inhibitors
  • Pyridines
  • Transcription Factor AP-1