Discovery of furopyridine-based compounds as novel inhibitors of Janus kinase 2: In silico and in vitro studies
Issued Date
2024-03-01
Resource Type
ISSN
01418130
eISSN
18790003
Scopus ID
2-s2.0-85183584639
Pubmed ID
38218283
Journal Title
International Journal of Biological Macromolecules
Volume
260
Rights Holder(s)
SCOPUS
Bibliographic Citation
International Journal of Biological Macromolecules Vol.260 (2024)
Suggested Citation
Suriya U., Mahalapbutr P., Geronikaki A., Kartsev V., Zubenko A., Divaeva L., Chekrisheva V., Petrou A., Oopkaew L., Somngam P., Choowongkomon K., Rungrotmongkol T. Discovery of furopyridine-based compounds as novel inhibitors of Janus kinase 2: In silico and in vitro studies. International Journal of Biological Macromolecules Vol.260 (2024). doi:10.1016/j.ijbiomac.2024.129308 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/95698
Title
Discovery of furopyridine-based compounds as novel inhibitors of Janus kinase 2: In silico and in vitro studies
Corresponding Author(s)
Other Contributor(s)
Abstract
Janus kinase 2 (JAK2), one of the JAK isoforms participating in a JAK/STAT signaling cascade, has been considered a potential clinical target owing to its critical role in physiological processes involved in cell growth, survival, development, and differentiation of various cell types, especially immune and hematopoietic cells. Substantial studies have proven that the inhibition of this target could disrupt the JAK/STAT pathway and provide therapeutic outcomes for cancer, immune disorders, inflammation, and COVID-19. Herein, we performed docking-based virtual screening of 63 in-house furopyridine-based compounds and verified the first-round screened compounds by in vitro enzyme- and cell-based assays. By shedding light on the integration of both in silico and in vitro methods, we could elucidate two promising compounds. PD19 showed cytotoxic effects on human erythroblast cell lines (TF-1 and HEL) with IC50 values of 57.27 and 27.28 μM, respectively, while PD12 exhibited a cytotoxic effect on TF-1 with an IC50 value of 83.47 μM by suppressing JAK2/STAT5 autophosphorylation. In addition, all screened compounds were predicted to meet drug-like criteria based on Lipinski's rule of five, and none of the extreme toxicity features were found. Molecular dynamic simulations revealed that PD12 and PD19 could form stable complexes with JAK2 in an aqueous environment, and the van der Waals interactions were the main force driving the complex formation. Besides, all compounds sufficiently interacted with surrounding amino acids in all crucial regions, including glycine, catalytic, and activation loops. Altogether, PD12 and PD19 identified here could potentially be developed as novel therapeutic inhibitors disrupting the JAK/STAT pathway.