Advancements in MPN Treatment: AJ1-10502, a Second-Generation JAK2 Inhibitor, Outperforms First-Generation Inhibitors in Preclinical Models

Type I JAK inhibitors are widely used for treating myelofibrosis and certain types of polycythemia vera, but their effectiveness can diminish over time due to sustained JAK/STAT signaling. A new type II JAK inhibitor, CHZ868, has shown promise in overcoming resistance to ruxolitinib (RUX) and reducing JAK2 allele burden, although it has limitations in terms of specificity and potential toxicity.

To address these issues, researchers have developed AJ1-10502, a novel type II JAK2 inhibitor with enhanced potency and selectivity. Using computational methods and structure-activity relationships, AJ1-10502 was identified and optimized for absorption, distribution, metabolism, and excretion. It showed significant JAK2 selectivity with minimal cross-reactivity compared to CHZ868.

In vitro studies indicated that AJ1-10502 effectively inhibited the proliferation of RUX-resistant cells, with an IC50 similar to that of RUX-sensitive cells. In vivo testing using a Jak2 knock-in/knock-out model demonstrated that AJ1-10502 could reduce leukocytosis and improve hematocrit and platelet levels, with spleen weight reductions comparable to genetic deletion of Jak2.

Importantly, AJ1-10502 was found to reduce the mutant allele fraction in peripheral blood and bone marrow, particularly within myeloid cell fractions, which was not observed with RUX. This suggests a targeted reduction in myeloid output. In a separate transplant model, AJ1-10502 confirmed its effects on leukocytosis, hematocrit, and spleen weight, and significantly reduced the mutant cell fraction in hematopoietic stem cells and progenitor populations.

A comparative study with CHZ868 showed that AJ1-10502 did not cause significant weight loss, indicating a comparable efficacy without systemic toxicity. Overall, AJ1-10502 is a potent and selective type II JAK2 inhibitor that offers improved efficacy and safety over previous JAK inhibitors. It has shown the potential to significantly reduce mutant cell fractions in vivo, which is a key advancement for the clinical development of type II JAK inhibitors for patients with myeloproliferative neoplasms.