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

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.