文章：

选择性JAK2V617F抑制剂NS-018在小鼠骨髓纤维化模型中的作用

Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis

原文发布日期：2014-01-10

DOI: 10.1038/bcj.2013.73

类型: Original Article

开放获取: 是

英文摘要：

A single somatic mutation, V617F, in Janus kinase 2 (JAK2) is one of the causes of myeloproliferative neoplasms (MPNs), including primary myelofibrosis, and the JAK2V617F mutant kinase is a therapeutic target in MPN. However, inhibition of wild-type (WT) JAK2 can decrease the erythrocyte or platelet (PLT) count. Our selective JAK2 inhibitor, NS-018, suppressed the growth of Ba/F3 cells harboring JAK2V617F more strongly than that of cells harboring WT JAK2. The 4.3-fold JAK2V617F selectivity of NS-018 is higher than the 1.0- to 2.9-fold selectivity of seven existing JAK2 inhibitors. NS-018 also inhibited erythroid colony formation in JAK2V617F transgenic mice at significantly lower concentrations than in WT mice. In keeping with the above results, in a JAK2V617F bone marrow transplantation mouse model with a myelofibrosis-like disease, NS-018 reduced leukocytosis and splenomegaly, improved bone marrow fibrosis and prolonged survival without decreasing the erythrocyte or PLT count in the peripheral blood. By exploring the X-ray co-crystal structure of NS-018 bound to JAK2, we identified unique hydrogen-bonding interactions between NS-018 and Gly993 as a plausible explanation for its JAK2V617F selectivity. These results suggest that NS-018 will have therapeutic benefit for MPN patients through both its efficacy and its reduced hematologic adverse effects.

摘要翻译： 

Janus激酶2（JAK2）的体细胞突变V617F是骨髓增殖性肿瘤（MPN，包括原发性骨髓纤维化）的病因之一，JAK2V617F突变激酶已成为MPN的治疗靶点。然而，抑制野生型（WT）JAK2可能导致红细胞或血小板计数减少。我们研发的选择性JAK2抑制剂NS-018对携带JAK2V617F的Ba/F3细胞增殖的抑制作用显著强于对野生型JAK2细胞。NS-018对JAK2V617F的选择性高达4.3倍，优于七种现有JAK2抑制剂的1.0至2.9倍选择性。在JAK2V617F转基因小鼠中，NS-018抑制红细胞集落形成所需的浓度显著低于野生型小鼠。与上述结果一致，在具有骨髓纤维化样疾病的JAK2V617F骨髓移植小鼠模型中，NS-018能改善白细胞增多和脾肿大，减轻骨髓纤维化并延长生存期，且未引起外周血红细胞或血小板计数下降。通过解析NS-018与JAK2结合的X射线共晶结构，我们发现NS-018与Gly993之间存在独特的氢键相互作用，这可能是其选择性抑制JAK2V617F的结构基础。这些结果表明，NS-018不仅具有治疗效能，还能降低血液学不良反应，将为MPN患者带来治疗获益。

原文链接：

Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis