2. Academic Validation
  3. Identification of Novel JAK2 Inhibitors from Amino Derivatives of Epoxyalantolactone: In Silico and In Vitro Studies

Identification of Novel JAK2 Inhibitors from Amino Derivatives of Epoxyalantolactone: In Silico and In Vitro Studies

  • Int J Mol Sci. 2025 Dec 28;27(1):329. doi: 10.3390/ijms27010329.
Duangjai Todsaporn 1,  Kamonpan Sanachai 2,  Chanat Aonbangkhen 3,  Rungtiva P Poo-Arporn 4,  Victor Kartsev 5,  Sergey Pukhov 6,  Svetlana Afanasyeva 6,  Athina Geronikaki 7,  Thanyada Rungrotmongkol 1 8
Affiliations

Affiliations

  • 1 Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
  • 2 Department of Biochemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand.
  • 3 Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
  • 4 Biological Engineering Program, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok 10140, Thailand.
  • 5 InterBioScreen, Chernogolovka 142432, Russia.
  • 6 Institute of Physiologically Active Compounds, Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia.
  • 7 Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
  • 8 Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.
PMID: 41516206 DOI: 10.3390/ijms27010329
Abstract

Janus kinase 2 (JAK2) is a key mediator of oncogenic signaling and a promising therapeutic target in cervical Cancer. This study employed a combination of in silico and in vitro approach to discover sesquiterpene lactone (SL) derivatives with JAK2 inhibitory activity. Molecular docking of forty SL derivatives, followed by drug-likeness and toxicity prediction, led to the selection of six candidates for synthesis and biological evaluation. Among these, SL10 (12.7 nM) and SL35 (21.7 nM) demonstrated potent JAK2 inhibition and exhibited selective cytotoxicity toward HeLa cervical Cancer cells, outperforming ruxolitinib. Flow cytometry confirmed Apoptosis induction and ROS elevation, suggesting ROS-mediated cytotoxic mechanisms. The 1 µs MD simulations demonstrated that both hydrogen bonding and hydrophobic interactions are critical determinants in stabilizing potent SLs-JAK2 complexes. These findings support SL10 and SL35 as promising scaffolds for further development of JAK2-targeted therapies in cervical Cancer.

Keywords

JAK inhibitor; MD simulations; kinase-targeted anticancer agents; lead optimization; molecular docking; sesquiterpene lactone-based scaffolds.

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