期刊
BIOMEDICINE & PHARMACOTHERAPY
卷 146, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2021.112459
关键词
Inflammation; CDK8; Kinase inhibitor; Structure-based virtual screening
资金
- Ministry of Science and Technology [MOST 108-2320-B-038-058-MY3, MOST 109-2320-B-002-049-MY3]
- Biomedical Translation Research Center, Academia Sinica [AS-BRPT-110-06]
- Health and welfare surcharge of tobacco products [MOHW110-TDU-B-212-144020]
- TMU Research Center of Cancer Translational Medicine from the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan
Research has identified new CDK8 inhibitors with potential in reducing the expression of inflammatory signaling mediators and low cytotoxicity in cell lines. One compound, F059-1017, showed higher selectivity and potency towards CDK8, making it a potential lead compound for developing novel anti-inflammatory therapeutics.
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.
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