Targeting JAK2V617F Mutation: INCB160058 as a Disease-Modifying Therapy in Preclinical MPN Models

The JAK2 V617F mutation is prevalent in myeloproliferative neoplasms (MPNs), including polycythemia vera, primary myelofibrosis, and essential thrombocythemia. While ruxolitinib has shown efficacy in treating MPNs by inhibiting JAK2 kinase activity, it does not reduce the JAK2 V617F mutation's presence or lead to a disease's molecular remission. A new agent, INCB160058, was developed to selectively target the JAK2V617F mutation, potentially leading to MPNs' functional cure.

The drug was designed with a high degree of specificity for the JAK2V617F's JH2 domain, showing a significant preference over the active kinase domain targeted by existing treatments. It was found to inhibit ligand-independent thrombopoietin receptor dimerization and reduce kinase activity through structural changes induced by its binding.

Experiments using CD34+ human stem cells from JAK2-mutant MF patients, engineered JAK2-mutant cancer cell lines, and murine cell lines demonstrated that INCB160058 selectively reduced abnormal cell activity and suppressed JAK2V617F+ cells without affecting healthy cells. In vivo studies in mice showed that the drug was well-tolerated and displayed antitumor effects, normalizing cytokine levels.

The findings suggest that INCB160058 can specifically target JAK2V617F-mutated cells, offering a potential therapeutic approach for MPNs that could lead to molecular remission and disease management.