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

研究成果: 雜誌貢獻文章同行評審

摘要

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.

原文英語
文章編號112459
期刊Biomedicine and Pharmacotherapy
146
DOIs
出版狀態已發佈 - 2月 2022

ASJC Scopus subject areas

  • 藥理

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