Discovery of a novel cyclin-dependent kinase 8 inhibitor with an oxindole core for anti-inflammatory treatment

Tony Eight Lin, Chia Ron Yang, Ching Hsuan Chou, Jui Yi Hsu, Min Wu Chao, Tzu Ying Sung, Jui Hua Hsieh, Wei Jan Huang, Kai Cheng Hsu

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic inflammation is an underlying cause in a number of diseases. Cyclin-dependent kinase 8 (CDK8) has been implicated as an inflammatory mediator, indicating its potential as an anti-inflammatory target. Herein, we performed structure-based virtual screening (SBVS) to identify novel CDK8 inhibitors. The pharmacological interactions for CDK8 were identified and incorporated into a SBVS protocol. Selected compounds were tested in enzymatic assays, and one compound was confirmed to be a CDK8 inhibitor with a 50% inhibitory concentration (IC50) value of 1684.4 nM. Comparing structural analogs identified a compound, F059–1017, with greater potency (IC50 558.1 nM). When tested in cell lines, the compounds displayed low cytotoxicity. Cellular assays revealed that the identified CDK8 inhibitors can reduce phosphorylation and expression of signaling mediators associated with inflammation. In addition, results of kinase profiling showed that compound F059–1017 is selective towards CDK8. These findings suggest that the new inhibitors have great potential as lead compounds for developing novel anti-inflammatory therapeutics.

Original languageEnglish
Article number112459
JournalBiomedicine and Pharmacotherapy
Volume146
DOIs
Publication statusPublished - Feb 2022

Keywords

  • CDK8
  • Inflammation
  • Kinase inhibitor
  • Structure-based virtual screening

ASJC Scopus subject areas

  • Pharmacology

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