NS-018: A Promising JAK2 Inhibitor for MPN Therapy in JAK2 V617F Mutant Mouse Model

A mutation in the JAK2 gene, characterized by the change from G to T at position 1849 leading to the JAK2 V617F variant, is frequently found in myeloproliferative neoplasms (MPNs) that do not have the Bcr-Abl gene. This mutation promotes cell growth without the need for cytokines and replicates the pathology seen in MPN patients, indicating that JAK2-targeting drugs could be beneficial. Several JAK2 inhibitors are currently being tested in clinical trials.

NS-018 is a new drug that targets JAK2 with high specificity and potency, showing an IC50 value below 1 nM and being more selective for JAK2 than other related enzymes. It was evaluated in a mouse model that develops MPN due to the JAK2 V617F mutation. These mice exhibit symptoms similar to human MPN, including high white and platelet counts, worsening anemia, organ enlargement, and bone marrow issues, along with weight loss and high mortality rates.

In vitro tests showed that NS-018 can inhibit the growth of red blood cell precursors and the activation of a key signaling protein, STAT5, in cells with the JAK2 V617F mutation. In the in vivo study, mice with established disease were treated with NS-018 at two different doses for 24 weeks. The treatment significantly improved survival and reduced weight loss. It also effectively lowered white blood cell counts and mitigated the progression of anemia and organ enlargement in a dose-dependent manner. The drug was particularly effective in reducing myeloid cells but had a milder impact on lymphocytes. Histopathological analysis showed a reduction in abnormal blood cell production in various organs, although it did not significantly affect bone marrow fibrosis or megakaryocyte overgrowth. Importantly, no significant side effects were noted in the treated mice.

Overall, NS-018 has shown promise in treating a mouse model of MPN caused by the JAK2 V617F mutation, closely resembling the human condition. It improved survival, weight, and several disease symptoms, supporting the potential of targeted therapy for JAK2 V617F-positive MPNs. Based on these findings, NS-018 is a strong candidate for further clinical evaluation in patients with MPNs that do not have the Bcr-Abl gene.