Discovering high-affinity type-II inhibitors of JAK2 with a structure-guided bioinformatics approach for cancer treatment

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase that plays a critical role in cytokine signaling via the JAK-STAT pathway. The aberrant activation of JAK2 due to genetic mutations or overexpression can lead to uncontrolled cell growth and survival, contributing to various cancers, including leukemia and myeloproliferative disorders. This makes JAK2 a promising therapeutic target for treating complex diseases such as cancer. Despite the development of ATP-competitive JAK2 inhibitors, these are limited by dose-dependent toxicities and reduced efficacy, particularly in cancers like myeloproliferative neoplasms (MPNs). To address these challenges, this study adopts a structure-based approach to identify novel JAK2 inhibitors with improved binding affinity and higher therapeutic potential. While Ruxolitinib has shown initial success in treating myelofibrosis and polycythemia vera, resistance and side effects necessitate the development of novel inhibitors. We screened the whole database of the PubChem library based on the structural similarity (≥90 % Tanimoto threshold) of the compounds with known JAK2 inhibitors, Ruxolitinib, AZD1480, Fedratinib, Momelotinib, and CHZ868. All the compounds from the PubChem database were further screened in molecular docking and ADMET evaluations. The molecular docking and molecular dynamics (MD) simulation showed that two compounds with PubChem CID:57568484 and CID:89019396 have great potential to be JAK2 inhibitors with appreciable binding affinity and stability in the active site pocket of the protein. Thus, the current work demonstrates the prospects of using CID:57568484 and CID:89019396 as a scaffold for developing novel JAK2 inhibitors, as well as providing information on their action mechanism and potential application in cancer therapeutics.