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

## TL;DR

This study identifies two new JAK2 inhibitors that show strong potential for treating cervical cancer by inducing cell death and outperforming existing drugs.

## Contribution

The study introduces novel JAK2 inhibitors derived from epoxyalantolactone with superior activity and selectivity for cervical cancer cells.

## Key findings

- SL10 and SL35 showed potent JAK2 inhibition with IC50 values of 12.7 nM and 21.7 nM, respectively.
- These compounds induced apoptosis and increased ROS in HeLa cells, indicating a ROS-mediated mechanism.
- MD simulations revealed hydrogen bonding and hydrophobic interactions stabilize SL-JAK2 complexes.

## 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.