Atavistik Bio Unveils Novel JAK2 V617F Mutant-Selective Inhibitors for Myeloproliferative Neoplasms at ASH 2025
核心洞察
Atavistik Bio (搜索) will present discovery of novel allosteric inhibitors that selectively target the JAK2 V617F (搜索) mutation while sparing wild-type JAK2 (搜索) at the ASH 2025 meeting.
The compounds demonstrate picomolar affinity for the JAK2 V617F (搜索) JH2 domain and greater than 100-fold selectivity over related JAK family kinases.
Preclinical data show potent inhibition of JAK2 V617F (搜索)-dependent signaling in cancer cell lines and strong target engagement in mouse tumor models.
Atavistik Bio (搜索) announced it will unveil the discovery of novel, potent, and selective allosteric inhibitors targeting the JAK2 V617F (搜索) mutation for treating myeloproliferative neoplasms (搜索) (MPNs) at the 67th American Society of Hematology (ASH) Annual Meeting in Orlando, December 6-9, 2025. The biotechnology company will present compelling preclinical data demonstrating the potential for these compounds to provide disease-modifying efficacy while avoiding off-target hematological effects associated with current treatments.
Addressing Critical Unmet Medical Need
The JAK2 V617F (搜索) mutation represents the most common driver mutation in MPN patients, affecting approximately 95% of patients with polycythemia vera (搜索), 60% of patients with essential thrombocythemia (搜索), and 55% of patients with myelofibrosis (搜索). Current approved pan-JAK inhibitors, such as ruxolitinib, target the active site in the JH1 kinase domain of JAK2 (搜索) but non-selectively inhibit both mutant and wild-type JAK2.
This broad inhibition limits the ability to significantly reduce JAK2 V617F (搜索) mutant allele burden, which correlates with disease progression. Additionally, inhibition of wild-type JAK2 (搜索) disrupts normal hematopoiesis, leading to adverse events and contributing to treatment discontinuation.
Novel Allosteric Approach Shows Promise
Atavistik Bio (搜索)'s JAK2 V617F (搜索) mutant-selective inhibitors bind the allosteric pseudokinase JH2 domain, which harbors the V617F mutation. The compounds were developed using the company's proprietary AMPS™ platform and structure-based drug design, demonstrating picomolar affinity for the JAK2 V617F JH2 domain and greater than 100-fold selectivity over related JAK family kinases including TYK2 and JAK1.
In preclinical models, these compounds showed potent inhibition of JAK2 V617F (搜索)-dependent signaling and proliferation in multiple human hematopoietic cancer cell lines harboring the mutations while sparing wild-type JAK2 (搜索) cells. The compounds demonstrated more than ten-fold selective inhibition of cytokine-independent JAK2 V617F signaling over cytokine-dependent wild-type JAK2 signaling in an isogenic cell model where the JAK2 V617F mutation was edited to wild-type.
Strong Preclinical Efficacy Data
In a mouse model bearing JAK2 V617F (搜索)-expressing SET2 tumors, Atavistik's JAK2 V617F selective inhibitors (搜索) demonstrated strong target engagement, evidenced by reduced phospho-STAT5 (搜索) levels. Compounds with favorable pharmacokinetic properties, good tolerability, and limited off-target activity are being advanced for further development.
"Unlike pan-JAK inhibitors that broadly target JAK2 (搜索) and can only manage symptoms of myeloproliferative neoplasms (搜索), our highly selective allosteric JAK2 V617F (搜索) mutant-selective inhibitors have the potential to deliver durable responses and mitigate off-target hematological effects, offering a powerful disease-modifying benefit and addressing the unmet needs of this patient population," said Marion Dorsch, Ph.D., President and Chief Scientific Officer at Atavistik Bio (搜索).
Clinical Development Pipeline
Atavistik Bio (搜索) is a clinical-stage biotechnology company currently conducting a Phase 1 clinical trial of ATV-1601, an allosteric selective inhibitor for solid tumors. The company is supported by top-tier investors including The Column Group, Nextech Invest, and Lux Capital.
The poster presentation titled "Discovery of JAK2V617F mutant specific allosteric inhibitors for the treatment of myeloproliferative neoplasms (搜索)" will be presented on Saturday, December 6, 2025, from 5:30 PM to 7:30 PM ET at the Orange County Convention Center.