Department of Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Kiyotake, Miyazaki, Japan.
Blood. 2011 Jun 23;117(25):6866-75. doi: 10.1182/blood-2010-01-262535. Epub 2011 Apr 29.
The activating mutations in JAK2 (including JAK2V617F) that have been described in patients with myeloproliferative neoplasms (MPNs) are linked directly to MPN pathogenesis. We developed R723, an orally bioavailable small molecule that inhibits JAK2 activity in vitro by 50% at a concentration of 2nM, while having minimal effects on JAK3, TYK2, and JAK1 activity. R723 inhibited cytokine-independent CFU-E growth and constitutive activation of STAT5 in primary hematopoietic cells expressing JAK2V617F. In an anemia mouse model induced by phenylhydrazine, R723 inhibited erythropoiesis. In a leukemia mouse model using Ba/F3 cells expressing JAK2V617F, R723 treatment prolonged survival and decreased tumor burden. In V617F-transgenic mice that closely mimic human primary myelofibrosis, R723 treatment improved survival, hepatosplenomegaly, leukocytosis, and thrombocytosis. R723 preferentially targeted the JAK2-dependent pathway rather than the JAK1- and JAK3-dependent pathways in vivo, and its effects on T and B lymphocytes were mild compared with its effects on myeloid cells. Our preclinical data indicate that R723 has a favorable safety profile and the potential to become an efficacious treatment for patients with JAK2V617F-positive MPNs.
在骨髓增殖性肿瘤（MPN）患者中发现的 JAK2（包括 JAK2V617F）激活突变与 MPN 的发病机制直接相关。我们开发了 R723，这是一种口服生物可利用的小分子，在 2nM 浓度下可使 JAK2 活性抑制 50%，而对 JAK3、TYK2 和 JAK1 活性的影响最小。R723 抑制了表达 JAK2V617F 的原代造血细胞中细胞因子非依赖性 CFU-E 生长和 STAT5 的组成性激活。在苯肼诱导的贫血小鼠模型中，R723 抑制了红细胞生成。在表达 JAK2V617F 的 Ba/F3 细胞白血病小鼠模型中，R723 治疗延长了生存期并减少了肿瘤负担。在模拟人类原发性骨髓纤维化的 V617F 转基因小鼠中，R723 治疗改善了生存期、肝脾肿大、白细胞增多和血小板增多。R723 在体内优先靶向 JAK2 依赖性通路，而不是 JAK1 和 JAK3 依赖性通路，与对髓样细胞的作用相比，其对 T 和 B 淋巴细胞的作用较轻。我们的临床前数据表明，R723 具有良好的安全性特征，并有可能成为 JAK2V617F 阳性 MPN 患者的有效治疗方法。
