JAK2V617F inhibitor

JAK2V617F inhibitors are a class of targeted small molecule therapies designed to selectively inhibit the V617F mutant form of Janus kinase 2 (JAK2), the primary driver of myeloproliferative neoplasms (MPNs). Unlike traditional JAK2 inhibitors (such as ruxolitinib) that target the catalytic JH1 kinase domain and often cause dose-limiting cytopenias by inhibiting wild-type JAK2, these next-generation inhibitors target the JH2 pseudokinase domain. By binding to the JH2 ATP pocket, these molecules allosterically inhibit the kinase activity of the mutant protein. This mechanism provides high selectivity for the JAK2V617F mutation over wild-type JAK2, potentially allowing for the elimination of mutant cells while sparing normal hematopoiesis. Research presented by AstraZeneca and Acerta B.V. indicates that these compounds show sub-nanomolar biochemical potency and significant cellular selectivity, with promising oral bioavailability in preclinical models.

Other names

JAK2V617F inhibitorJAK-2V617F inhibitorJAK 2V617F inhibitorselective JAK2V617F inhibitorJAK2 JH2 domain inhibitorJAK-2 JH2 domain inhibitorJAK 2 JH2 domain inhibitor