Discovery of a novel cyclin-dependent kinase 8 inhibitor with an oxindole core for anti-inflammatory treatment - 16/01/22

Doi : 10.1016/j.biopha.2021.112459

Tony Eight Lin ^a,^b,^{^{1
These authors contributed equally to this work.}}, Chia-Ron Yang ^c,^{^{1
These authors contributed equally to this work.}}, Ching-Hsuan Chou ^c, Jui-Yi Hsu ^a,^d, Min-Wu Chao ^c, Tzu-Ying Sung ^e, Jui-Hua Hsieh ^f, Wei-Jan Huang ^g,^h, Kai-Cheng Hsu ^a,^d,^g,^i,^j,^k,^⁎
^a Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
^b Master Program in Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
^c School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
^d Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
^e Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
^f Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA
^g Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
^h Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
ⁱ Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
^j TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
^k TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan

^⁎Corresponding author at: Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical UniversityTaipeiTaiwan

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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.

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Highlights

•	CDK8 is involved in the innate immune and inflammatory response.
•	A structure-based virtual screening protocol was performed to identify novel CDK8 inhibitors.
•	A potent CDK8 inhibitor was identified and compared to selected analogs.
•	An interaction analysis elucidated the hit compounds binding interactions.
•	In vitro assays show inhibitors modulate mediators associated with inflammation.

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Keywords : Inflammation, CDK8, Kinase inhibitor, Structure-based virtual screening

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Discovery of a novel cyclin-dependent kinase 8 inhibitor with an oxindole core for anti-inflammatory treatment - 16/01/22

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