ZE74-0282

ZE74-0282 is a first-in-class, wild-type–sparing, small-molecule Janus kinase 2 (JAK2) inhibitor that selectively targets the JH2 pseudokinase domain of mutant JAK2 V617F while preserving signaling of wild-type JAK2 and other JAK family kinases.[1][3][7] Rationally designed using in silico and AI-driven molecular pharmacology by Eilean Therapeutics, the compound shows picomolar potency and >500-fold selectivity for JAK2 V617F JH2 over wild-type JAK2 JH2, with marked inhibition of pSTAT5 signaling and proliferation in JAK2 V617F–driven cell models and minimal effects on normal hematopoietic cells.[1][3] In preclinical myeloproliferative neoplasm models, ZE74-0282 demonstrates selective suppression of JAK2 V617F/ASXL1-mutant progenitors, strong in vivo tumor growth inhibition, and a broad therapeutic window, supporting its development as a potentially disease-modifying therapy for JAK2 V617F–mutated polycythemia vera, essential thrombocytosis, myelofibrosis, and related myeloid malignancies.[1][3][5][7] Eilean Therapeutics plans to initiate first-in-human clinical studies of ZE74-0282 in late 2025, advancing it from preclinical evaluation toward clinical development in JAK2 V617F–driven myeloproliferative disorders.[1][3][4][7]