Eilean Therapeutics Advances ZE74-0282, a Highly Selective Inhibitor of Mutated JAK2 V617F, into First-in-Human Clinical Development
DOVER, Del., Dec. 17, 2025 /PRNewswire/ — Eilean Therapeutics announced the advancement of ZE74-0282 into first-in-human clinical development. ZE74-0282 is a novel, highly selective inhibitor of the mutated Janus kinase 2 (JAK2) V617F variant and is being developed as a differentiated therapeutic candidate for myeloproliferative neoplasms, including myelofibrosis.
ZE74-0282 was discovered using Eilean Therapeutics’ proprietary rational drug design approach, incorporating parallel and iterative optimization of biochemical potency, mutant selectivity, off-target liability, pharmacokinetics, and oral bioavailability. This integrated discovery strategy was intended to achieve durable on-target efficacy while minimizing inhibition of wild-type JAK2 and other kinases that contribute to dose-limiting toxicities observed with existing JAK inhibitors.
The initiation of clinical development follows a comprehensive nonclinical data package demonstrating strong potency, exceptional mutant selectivity, favourable pharmacology, and a supportive safety profile, together supporting the potential for an improved therapeutic index relative to currently available JAK inhibitors.
ZE74-0282 demonstrated low-nanomolar potency against JAK2 V617F–dependent signal transducer and activator of transcription 5 (STAT5) phosphorylation, a central oncogenic signalling pathway in myeloproliferative neoplasms. Robust on-target activity was observed across JAK2 V617F–mutant cellular models, including HEL and SET-2 cell lines.
A defining feature of ZE74-0282 is its exceptional selectivity for the mutated JAK2 V617F variant over wild-type JAK2. Across multiple biochemical and cellular assays, including STAT5 phosphorylation and cytotoxicity readouts, ZE74-0282 achieved up to a five-hundred-fold selectivity relative to wild-type JAK 2. “This selectivity profile reflects deliberate structure-based optimization to balance potency against the mutant target with minimization of off-target kinase inhibition that may compromise normal hematopoiesis,” commented Iain Dukes M.A., D.Phil., Chief Executive Officer of Eilean Therapeutics.
In whole blood assays using samples derived from patients with myelofibrosis harboring confirmed JAK2 V617F mutations, ZE74-0282 demonstrated superior mutant selectivity compared with ruxolitinib, enhanced activity against mutated myeloid populations, and minimal impact on non-mutant cells, consistent with selective targeting of malignant clones.
An IND application has been submitted to support first-in-human clinical studies of ZE74-0282. The initial clinical study is designed as a single ascending dose trial in healthy volunteers, with objectives to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and target engagement. Enrollment in the first-in-human study is planned to begin in the first quarter of 2026.
In parallel, Eilean Therapeutics is preparing for subsequent clinical studies in patients with myelofibrosis and other myeloproliferative disorders, with the intent to transition efficiently from healthy volunteer evaluation into patient-based studies focused on JAK2 V617F–driven disease. ZE74-0282 is being developed as a once-daily oral therapy.
“ZE74-0282 reflects a deliberate, design-driven strategy to address the limitations of existing JAK inhibitors,” commented John C Byrd, M.D., Chief Medical Officer of Eilean Therapeutics. “By optimizing mutant selectivity, pharmacology, and safety in parallel during discovery, we believe ZE74-0282 has the potential to deliver sustained target engagement with an improved benefit-risk profile as we move into clinical evaluation.”
About Eilean Therapeutics
Eilean Therapeutics is a biotechnology company focused on the discovery and development of small-molecule therapies targeting genetically defined drivers of disease. The company’s pipeline is built on proprietary rational design capabilities and deep mechanistic insight, with the objective of generating differentiated clinical candidates for haematologic and metabolic disorders.
Forward-Looking Statements
This communication contains forward-looking statements regarding the development, potential clinical utility, and future plans for ZE74-0282. Such statements are based on current expectations and assumptions and are subject to risks and uncertainties inherent in drug development, clinical trial execution, regulatory review, and commercialisation. Actual results may differ materially from those anticipated. Eilean Therapeutics undertakes no obligation to update these statements except as required by law.
Contact:
Amy Burd
Chief Scientific Officer
Eilean Therapeutics
Email: [email protected]
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SOURCE Eilean Therapeutics
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