BACKGROUND

The JAK2 mutation plays a crucial part in the pathogenesis of myeloproliferative neoplasms (MPN), which includes polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) leading to aberrant proliferation and survival of hematopoietic cells. Alongside the challenges of drug resistance and side effects, identifying novel compounds that selectively target JAK2 could provide more effective and safer therapeutic options for patients with MPNs.

MATERIALS AND METHODS

We employed computational approaches like high-throughput virtual screening, molecular dynamics simulations (MDS), and binding free energy calculations to identify inhibitors targeting wild and mutant JAK2 kinases. JAK2 positive HEL, wild type JAK2 positive TF-1, and non-cancerous Vero cells were used for validations.

RESULTS

SBLJ23 emerged as a top candidate inhibitor with specificity for JAK2. Protein-ligand interaction studies and MDS revealed stable interactions and binding of SBLJ23 over the simulation period, with Root Mean Square Deviation (RMSD) indicating consistent binding after 1t15ns. SBLJ23 displayed a half maximal inhibitory concentration (IC) value of 522.4 nM against the JAK2 enzyme. The compound exhibited inhibition of cell proliferation in HEL and TF-1 cells, with half maximal cell growth inhibitory concentration (GI) values of 2.51 and 15.87 µM, respectively. Moreover, SBLJ23 induced G/M cell cycle arrest in HEL cells to facilitate apoptosis in these cell lines. The compound significantly reduced the percentage of phospho JAK2 and phospho STAT3 in HEL cells.

CONCLUSION

High binding affinity, stable interaction profile, favorable binding free energy, and validations claim SBLJ23 as a potential lead compound against JAK2 and suggest further development and optimization towards clinical application in managing myeloproliferative neoplasms.