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Article

In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones

by
Kamonpan Sanachai
1,
Panupong Mahalapbutr
2,
Lueacha Tabtimmai
3,
Supaphorn Seetaha
4,
Nantawat Kaekratoke
5,
Supakarn Chamni
6,7,
Syed Sikander Azam
8,
Kiattawee Choowongkomon
4,* and
Thanyada Rungrotmongkol
1,9,*
1
Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
2
Department of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
3
Department of Biotechnology, Faculty of Applied Science, King Mongkut’s University of Technology of North Bangkok, Bangkok 10800, Thailand
4
Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand
5
Department of Materials Science and Engineering, Vidyasirimedhi Institute of Science and Technology (VISTEC), Rayong 21210, Thailand
6
Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
7
Natural products and Nanoparticles Research Unit (NP2), Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
8
Computational Biology Lab, National Center for Bioinformatics, Quaid-i-Azam University, Islamabad 45320, Pakistan
9
Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(2), 597; https://doi.org/10.3390/molecules28020597
Submission received: 29 November 2022 / Revised: 30 December 2022 / Accepted: 4 January 2023 / Published: 6 January 2023
(This article belongs to the Special Issue New Insights into Kinase Inhibitors II)
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Abstract

Janus kinases (JAKs) are involved in numerous cellular signaling processes related to immune cell functions. JAK2 and JAK3 are associated with the pathogenesis of leukemia and common lymphoid-derived illnesses. JAK2/3 inhibitors could reduce the risk of various diseases by targeting this pathway. Herein, the naphthoquinones were experimentally and theoretically investigated to identify novel JAK2/3 inhibitors. Napabucasin and 2′-methyl napabucasin exhibited potent cell growth inhibition in TF1 (IC50 = 9.57 and 18.10 μM) and HEL (IC50 = 3.31 and 6.65 μM) erythroleukemia cell lines, and they significantly inhibited JAK2/3 kinase activity (in a nanomolar range) better than the known JAK inhibitor, tofacitinib. Flow cytometric analysis revealed that these two compounds induced apoptosis in TF1 cells in a time and dose-dependent manner. From the molecular dynamics study, both compounds formed hydrogen bonds with Y931 and L932 residues and hydrophobically contacted with the conserved hinge region, G loop, and catalytic loop of the JAK2. Our obtained results suggested that napabucasin and its methylated analog were potential candidates for further development of novel anticancer drug targeting JAKs.
Keywords: JAK2/3 inhibitors; naphthoquinones; enzymatic and cell-based assay; molecular dynamics simulations JAK2/3 inhibitors; naphthoquinones; enzymatic and cell-based assay; molecular dynamics simulations
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MDPI and ACS Style

Sanachai, K.; Mahalapbutr, P.; Tabtimmai, L.; Seetaha, S.; Kaekratoke, N.; Chamni, S.; Azam, S.S.; Choowongkomon, K.; Rungrotmongkol, T. In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones. Molecules 2023, 28, 597. https://doi.org/10.3390/molecules28020597

AMA Style

Sanachai K, Mahalapbutr P, Tabtimmai L, Seetaha S, Kaekratoke N, Chamni S, Azam SS, Choowongkomon K, Rungrotmongkol T. In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones. Molecules. 2023; 28(2):597. https://doi.org/10.3390/molecules28020597

Chicago/Turabian Style

Sanachai, Kamonpan, Panupong Mahalapbutr, Lueacha Tabtimmai, Supaphorn Seetaha, Nantawat Kaekratoke, Supakarn Chamni, Syed Sikander Azam, Kiattawee Choowongkomon, and Thanyada Rungrotmongkol. 2023. "In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones" Molecules 28, no. 2: 597. https://doi.org/10.3390/molecules28020597

APA Style

Sanachai, K., Mahalapbutr, P., Tabtimmai, L., Seetaha, S., Kaekratoke, N., Chamni, S., Azam, S. S., Choowongkomon, K., & Rungrotmongkol, T. (2023). In Silico and In Vitro Study of Janus Kinases Inhibitors from Naphthoquinones. Molecules, 28(2), 597. https://doi.org/10.3390/molecules28020597

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