A novel CDK8 inhibitor with poly-substituted pyridine core: Discovery and anti-inflammatory activity evaluation in
Xing Chen1, Yaoyao Yan1, Xiu Cheng2
1School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, PR China.
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.
Insights
Researchers developed novel poly-substituted pyridine derivatives as cyclin-dependent kinase 8 (CDK8) inhibitors. Compound CR16 effectively reduces inflammation by increasing Interleukin-10 (IL-10) levels, showing promise for treating inflammatory bowel disease (IBD).
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Molecular Biology
Background:
- Cyclin-dependent kinase 8 (CDK8) is a key target for anti-inflammatory drug development.
- CDK8 inhibition enhances Interleukin-10 (IL-10) production via activator protein-1 (AP-1) activation, a potential therapeutic strategy for inflammatory bowel disease (IBD).
Purpose of the Study:
- To design and synthesize novel poly-substituted pyridine derivatives as potent CDK8 inhibitors.
- To evaluate the therapeutic efficacy of these compounds in preclinical models of IBD.
Main Methods:
- Structure-based drug design and dominant fragment hybridization were employed for compound synthesis.
- In vitro assays assessed CDK8 inhibition, AP-1 transcriptional activity, and IL-10 expression.
- In vivo studies evaluated compound efficacy in an animal model of IBD and analyzed relevant signaling pathways (TLR7/NF-κB/MAPK, IL-10-JAK1-STAT3).
Main Results:
- Compound CR16 demonstrated significant inhibitory activity against CDK8 (IC50 = 74.4 nM).
- CR16 enhanced AP-1 transcriptional activity and increased IL-10 abundance in vitro and in vivo.
- CR16 modulated key inflammatory signaling pathways and exhibited potent therapeutic effects in a preclinical IBD model.
Conclusions:
- The synthesized poly-substituted pyridine derivatives, particularly CR16, are effective CDK8 inhibitors.
- CR16 demonstrates therapeutic potential for inflammatory bowel disease by modulating IL-10 production and related signaling pathways.
Related Concept Videos
02:34Inhibition of Cdk Activity
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
01:23Dipeptidyl Peptidase 4 Inhibitors