Undisclosed JAK2V617F inhibitor / AstraZeneca - LARVOL DELTA

Identification of novel, potent, and selective JAK2V617F inhibitors (ASH 2025) - "We found moleculeswith sub-micromolar potencies on STAT5 transcriptional activity and proliferation with >10-fold selectivityover WT JAK2.Molecules with encouraging cellular selectivity were then assayed for their activity on other signalingpathways driven by heterodimers formed by other JAK-family members, against other kinases, andprofiled across a panel of 16 hematological cancer cell lines from myeloid and lymphoid lineages.Compared to ruxolitinib, our molecules were >3-fold less active on other JAK-family members with asimilar cell panel profile, which indicate improved selectivity. In summary, our comprehensive screening cascades allow for the discovery of compounds with strongselectivity at both biochemical and cellular levels. Using this approach, we identified novel, potent, andselective JAK2V617F inhibitors."

Essential Thrombocythemia • Hematological Malignancies • Myelofibrosis • Polycythemia Vera • Thrombocytopenia • STAT5