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Eilean Therapeutics to Present ZE74-0282 at ASH 2025

Eilean Therapeutics LLC, a cutting-edge biotechnology firm focused on advancing precision medicines for diseases such as cancer and immune-inflammatory conditions, has announced that it will showcase its revolutionary JAK2-JH2/V617F inhibitor, ZE74-0282, at the upcoming 67th Annual Meeting of the American Society of Hematology (ASH) in 2025. Alongside the presentation of promising preclinical data, the company will also commence its first-in-human clinical trials for this novel therapy in December 2025.

Background on JAK2 and its Implications for Hematological Cancers

The JAK2 V617F mutation is identified as one of the primary recurring driver mutations linked to classical myeloproliferative neoplasms (MPNs), which encompass disorders like polycythemia vera, essential thrombocytosis, and myelofibrosis. This mutation is known to lead to persistent hyperactivation of JAK2 signaling, which is critical for the proliferation and survival of blood cells. Current treatment options such as ruxolitinib and fedratinib target the JH1 kinase domain of JAK2, providing symptomatic relief but at the expense of affecting normal wild-type JAK2 signaling necessary for healthy blood cell production. This unintended non-selective inhibition can limit the long-term effectiveness and tolerability of existing therapies.

Introducing ZE74-0282: A New Hope for Patients

The star of the presentation at ASH 2025, ZE74-0282, is an innovative small-molecule inhibitor that has been carefully crafted through advanced in-silico techniques alongside AI-driven molecular pharmacology approaches. This unique design enables ZE74-0282 to specifically target the JH2 domain of the mutant JAK2 V617F, allowing it to spare the wild-type JAK2 as well as other JAK family members. This level of specificity is anticipated to significantly improve the therapeutic index when compared to previous JAK inhibitors.

Key Preclinical Findings

In preclinical studies, ZE74-0282 exhibited remarkable potency and selectivity:

• - Potency: Achieved picomolar levels of effectiveness with over 500-fold selectivity towards JAK2 V617F JH2 in cellular models.
• - Selective Signaling Inhibition: Demonstrated a 100-fold inhibition rate of pSTAT5 phosphorylation in cells harboring JAK2 V617F, while having minimal effects on wild-type cell lines.
• - Specificity in Human Assays: Showed nanomolar potency in reducing activation of pSTAT5 within myeloid cells from patients with JAK2 V617F-positive MPNs, confirming wild-type sparing.
• - Enhanced In Vivo Activity: Outperformed fedratinib in xenograft models, showcasing superior tumor growth inhibition and pSTAT5 suppression.
• - Safety Profile: Presented a favorable pharmacokinetic and toxicological profile, suggesting a wide therapeutic window conducive to optimal clinical dosing.

Conclusions and Future Directions

ZE74-0282 is more than just another therapy; it represents a first-in-class JAK2 inhibitor specifically targeting the JH2 domain while preserving normal hematopoietic signaling. This discriminating selectivity, coupled with positive pharmacological properties, positions ZE74-0282 as a promising potential treatment for individuals suffering from JAK2 V617F-associated myeloproliferative disorders.

Eilean Therapeutics is enthusiastic about initiating its first human clinical trials for ZE74-0282 in December 2025, aiming to progress towards potentially offering a disease-modifying therapy for this challenging group of malignancies.

About Eilean Therapeutics

Eilean Therapeutics LLC operates as a private biopharmaceutical entity committed to discovering and developing best-in-class and first-in-class small-molecule therapies. These focus on genetic and signaling weaknesses across various types of malignancies including hematologic cancers, solid tumors, and chronic inflammatory disorders. The diverse Eilean pipeline consists of selective kinase inhibitors, molecular degraders, and innovative anti-inflammatory strategies designed to effect lasting disease modification.