文章：

NS-018是一种强效和选择性的JAK2/Src抑制剂，在原代细胞和骨髓增殖性肿瘤小鼠模型中的疗效

Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms

原文发布日期：2011-07-22

DOI: 10.1038/bcj.2011.29

类型: Original Article

开放获取: 是

英文摘要：

Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC50) of <1 nM, and had 30–50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL–JAK2 fusion gene; IC50=11–120 nM), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs.

摘要翻译： 

由JAK2体细胞突变（JAK2V617F）或血小板生成素受体突变（MPLW515L）引起的Janus激酶2（JAK2）异常激活在骨髓增殖性肿瘤（MPN）的发病机制中起关键作用，这表明抑制异常JAK2激活将具有治疗益处。我们新型JAK2抑制剂NS-018对JAK2具有高度活性，其半数抑制浓度（IC50）小于1 nM，并且对JAK2的选择性比其他JAK家族激酶（如JAK1、JAK3和酪氨酸激酶2）高30-50倍。除JAK2外，NS-018还抑制Src家族激酶。NS-018对表达组成型激活JAK2的细胞系（JAK2V617F或MPLW515L突变或TEL-JAK2融合基因）表现出有效的抗增殖活性（IC50=11-120 nM），但对大多数没有组成型激活JAK2的造血细胞系仅显示最小细胞毒性。此外，NS-018优先抑制真性红细胞增多症患者体外红细胞生成素非依赖性内源性集落形成。NS-018还显著减轻携带JAK2V617F的Ba/F3细胞接种小鼠的脾肿大并延长其生存期。此外，在JAK2V617F转基因小鼠中，NS-018显著减少白细胞增多、肝脾肿大和髓外造血，改善营养状况并延长生存期。这些结果表明NS-018有望成为治疗骨髓增殖性肿瘤的候选药物。

原文链接：

Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms