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

• Published in: Journal of Saudi Chemical Society 2022-07, Vol.26 (4), p.101516, Article 101516
• Main Authors: Reyad-ul-Ferdous, Md, Abdalla, Mohnad, Yang, Mengjiao, Xiaoling, Li, Bian, Wenbo, Xie, Jin, Song, Yongfeng
• Format: Article
• Language: English
• Subjects: Brown fat thermogenesis; Cell viability; In silico study; Mitochondrial function; Obesity; Screening of epigenetic drug Libraries; UCP1 regulatory mechanism
• ISSN: 1319-6103
• DOI: 10.1016/j.jscs.2022.101516

[Display omitted] 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. 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. 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. 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.