DOVER, Del., Nov. 6, 2025 /PRNewswire/ — Eilean Therapeutics LLC, a biotechnology company developing next-generation precision medicines for cancer and immune-inflammatory diseases, today announced the upcoming presentation of preclinical data for its first-in-class, wild-type–sparing JAK2-JH2/V617F inhibitor ZE74-0282 at the 67th American Society of Hematology (ASH) Annual Meeting. The company also confirmed plans to initiate first-in-human clinical studies in December 2025.
Background
The JAK2 V617F mutation is the most common recurring driver mutation in classical myeloproliferative neoplasms (MPNs)—including polycythemia vera, essential thrombocytosis, and myelofibrosis—and is also present in subsets of other myeloid malignancies. The mutation, located in the JH2 pseudokinase domain, causes constitutive hyperactivation of JAK2 signaling.
Approved JAK inhibitors such as ruxolitinib and fedratinib target the JH1 kinase domain, offering symptomatic relief but lacking selectivity for the mutant form. This non-selective inhibition disrupts wild-type (WT) JAK2 signaling essential for normal hematopoiesis, limiting both long-term efficacy and tolerability.
About ZE74-0282
ZE74-0282 is a novel, small-molecule inhibitor rationally designed through in-silico and AI-driven molecular pharmacology to selectively target the JH2 domain of mutant JAK2 V617F while sparing WT JAK2 and other JAK family kinases.
Key non-clinical findings include:
- Picomolar potency and > 500-fold selectivity for JAK2 V617F JH2 versus WT JAK2 JH2 in cellular assays.
- 100× selective inhibition of pSTAT5 phosphorylation and proliferation in BaF3 JAK2 V617F and SET-2 JAK2 V617F cells, with minimal effect on WT cells.
- Nanomolar potency in selectively reducing pSTAT5 in myeloid cells from human JAK2 V617F⁺ MPN whole-blood assays, with no effect on lymphoid cells—confirming wild-type sparing. In contrast, ruxolitinib suppressed signaling across both lineages.
- Selective inhibition of colony formation from JAK2 V617F/ASXL1-mutant progenitors, without affecting WT JAK2 progenitors, in murine colony-forming assays.
- Superior tumor growth inhibition and stronger in-vivo pSTAT5 suppression compared with fedratinib in xenograft models.
- Linear pharmacokinetics and toxicokinetics in DRF and GLP toxicology studies, demonstrating safety, tolerability, and a broad therapeutic window supporting optimal clinical dose selection.
Conclusion
ZE74-0282 is the first-in-class, JH2-domain–specific JAK2 inhibitor that selectively targets mutant JAK2 V617F while preserving normal JAK2-mediated hematopoietic signaling. Its differentiated selectivity profile and favorable pharmacology indicate a superior therapeutic index compared with JH1-directed inhibitors. These data support ZE74-0282 as a potentially disease-modifying therapy for patients with JAK2 V617F-driven myeloproliferative disorders.
Eilean Therapeutics plans to initiate its first-in-human clinical study of ZE74-0282 in December 2025.
About Eilean Therapeutics LLC
Eilean Therapeutics LLC is a privately held biopharmaceutical company dedicated to discovering and developing best-in-class and first-in-class small-molecule therapies that target genetic and signaling vulnerabilities across hematologic malignancies, solid tumors, and chronic inflammatory diseases. The company’s pipeline includes selective kinase inhibitors, molecular degraders, and novel anti-inflammatory mechanisms designed to deliver durable disease modification.
Contact:
Amy Burd, PhD — Chief Scientific Officer
Eilean Therapeutics LLC
Dover, DE, USA
[email protected]
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