Epigenetic drug (XL019) JAK2 inhibitor increases mitochondrial function in brown adipocytes by upregulating mitochondrial uncoupling protein 1 (UCP1), screening of epigenetic drug libraries, cell viability, and in-silico studies

Md. Reyad-ul-Ferdous; Mohnad Abdalla; Mengjiao Yang; Li Xiaoling; Wenbo Bian; Jin Xie; Yongfeng Song

Journal of Saudi Chemical Society (Jul 2022)

Epigenetic drug (XL019) JAK2 inhibitor increases mitochondrial function in brown adipocytes by upregulating mitochondrial uncoupling protein 1 (UCP1), screening of epigenetic drug libraries, cell viability, and in-silico studies

Md. Reyad-ul-Ferdous,
Mohnad Abdalla,
Mengjiao Yang,
Li Xiaoling,
Wenbo Bian,
Jin Xie,
Yongfeng Song

Affiliations

Md. Reyad-ul-Ferdous: Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, PR China; Department of Internal Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, PR China; Shandong Institute of Endocrinology & Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, PR China; Corresponding authors at: Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, PR China.
Mohnad Abdalla: Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, PR China
Mengjiao Yang: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong, PR China
Li Xiaoling: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong, PR China
Wenbo Bian: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong, PR China
Jin Xie: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong, PR China
Yongfeng Song: Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, PR China; Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong 250021, PR China; Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong, PR China; Shandong Institute of Endocrinology & Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong 250021, PR China; Corresponding authors at: Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, PR China.

Journal volume & issue: Vol. 26, no. 4
p. 101516

Abstract

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Background: At present lacking of effective and safe anti-obesity drugs available leads to initiate obesity worldwide that promotes several diseases like cardiovascular diseases, liver diseases, and NASH. The development of new therapeutics is an emergency demand to cure obesity-related diseases. Mitochondrial uncoupling protein 1 (UCP1) gene could be a potential target to develop new drug moieties that can treat obesity-related diseases. Methods: We used a GFP reporter cell line to screen epigenetic drug libraries to identify UCP1 regulators that could be effective drug candidates to treat obesity-related diseases. In this study, we employed an in-silico study that revealed drug-protein interaction and stability of drugs with protein. Results: Screening epigenetic drug libraries, we identified XL019 significant TYK2, JAK2, and JAK3, inhibitors that can significantly promote UCP1 gene expression in brown adipocytes. Here, we found that XL019 plays a vital role to modulates mitochondrial function and could be beneficial against obesity. Further analysis shows that XL019 significantly improved mitochondrial ATP production and mitochondrial DNA copy number of adipocytes compared with the control group. The in-silico study demonstrated drug-protein interaction and binding side with UCP1 gene. Thus XL019 improves mitochondrial function that would be effective drug candidate to treat metabolic diseases and obesity-related diseases. Conclusion: In this study, we confirm the potential effect of the XL019 epigenetic drug that modulates mitochondrial function and in-silico study on drug-likeness, stability, and safety profile. Further investigation will reveal the new insight into the mechanism of action against obesity, metabolic diseases ( NASH, Fibrosis, cardiac diseases and so on), by modulation of the mitochondrial UCP1 gene and mitochondrial function.

Published in Journal of Saudi Chemical Society

ISSN: 1319-6103 (Print)
Publisher: Elsevier
Country of publisher: Saudi Arabia
LCC subjects: Science: Chemistry
Website: http://www.journals.elsevier.com/journal-of-saudi-chemical-society/

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