Epigallocatechin Gallate as a Targeted Therapeutic Strategy Against the JAK2V617F Mutation: New Perspectives for the Treatment of Myeloproliferative Neoplasms and Acute Myeloid Leukemia

The JAK2V617F mutation is a major molecular factor in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and has been increasingly associated with clonal progression to acute myeloid leukemia (AML), resulting in a poorer prognosis and resistance to conventional therapies. This study integrates a comprehensive literature review with bioinformatic approaches to investigate the potential inhibitory activity of Epigallocatechin Gallate (EGCG), a green tea polyphenol widely recognized for its antioxidant and anticancer properties, on the JAK2V617F mutation. Clinical data from case reports demonstrated heterogeneity in disease progression and frequent therapeutic failures. Molecular docking analysis using the Janus Kinase 2 (JAK2) protein structure (PDB ID: 6D2I) identified a high-affinity binding pocket for EGCG near the V617F mutation site. EGCG exhibited strong binding affinity (−9.2 kcal/mol), forming key interactions with residues Lys581, Ile559, and Leu680, suggesting allosteric modulation of the JH2 pseudokinase domain. To validate our docking protocol, redocking of the known inhibitor AT9283 yielded a favorable Root Mean Square Deviation (RMSD) 2.683 Å and binding energy (−8.3 kcal/mol), confirming the reliability of our approach. Notably, EGCG demonstrated superior binding affinity compared to AT9283 and targets a distinct allosteric site, highlighting its unique mechanism of action and potential as a selective allosteric inhibitor. These findings position EGCG as a promising candidate for future preclinical evaluation, offering a novel strategy to overcome therapy resistance in JAK2V617F-driven malignancies.