The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.

中文翻译：

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发现了5-氯-N ² -[（（1 S）-1-（5-氟嘧啶-2-基）乙基] -N ^4-（5-甲基-1 H-吡唑-3-基）嘧啶-2， 4-二胺（AZD1480）作为Jak / Stat途径的新型抑制剂

骨髓增生性肿瘤，真性红细胞增多症，原发性血小板增多症和特发性骨髓纤维化是异质性但相关的一组血液恶性肿瘤，其特征是一个或多个骨髓谱系的克隆扩增。Jak2 V617F功能突变获得的发现突显了Jak2作为MPN中的潜在治疗靶标。在这里，我们公开了一系列吡唑-3-基嘧啶-4-胺的发现，以及9e（AZD1480）作为强效Jak2抑制剂的鉴定。图9e抑制信令和Jak2的V617F细胞系的增殖在体外，表明在体内 在TEL-Jak2模型中具有有效的功效，具有出色的物理特性和临床前药代动力学，目前正在I期临床试验中进行评估。