Discovery of Potent and Orally Effective Dual Janus Kinase 2/FLT3 Inhibitors for the Treatment of Acute Myelogenous Leukemia and Myeloproliferative Neoplasms
Discovery of Potent and Orally Effective Dual Janus Kinase 2/FLT3 Inhibitors for the Treatment of Acute Myelogenous Leukemia and Myeloproliferative Neoplasms
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发现有效且口服有效的双 Janus 激酶 2/FLT3 抑制剂，用于治疗急性髓性白血病和骨髓增殖性肿瘤
DOI：
10.1021/acs.jmedchem.9b01348
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发表时间：
2019
影响因子：
7.3
通讯作者：
Chen Lijuan
中科院分区：
文献类型：
--
作者：
Yang Tao;Hu Mengshi;Qi Wenyan;Yang Zhuang;Tang Minghai;He Jun;Chen Yong;Bai Peng;Yuan Xue;Zhang Chufeng;Liu Kongjun;Lu Yulin;Xiang Mingli;Chen Lijuan
在这里，我们描述了一系列独特的4-(1H-吡唑-4-基)-嘧啶-2-胺衍生物的设计、合成和构效关系，这些衍生物可以选择性地抑制Janus Kinase 2(JAK2)和Flt3激酶。这些筛选级联反应表明，18E是首选化合物，JAK2和Flt3的IC50值分别为0.7和4 nM。此外，18E是一种有效的JAK2抑制剂，对JAK1和JAK3的选择性分别是JAK1和JAK3的37倍和56倍，并且与其他100种代表性的激酶相比具有很好的选择性。在一系列细胞因子刺激的细胞检测中，18E表现出比其他JAK亚型更高的JAK2选择性。灌胃给药60 mg/kg可明显抑制肿瘤生长，对MV4-11和SET-2移植瘤模型的抑瘤率分别为93%和85%。此外，18具有良好的生物利用度(F=58%)、合适的半衰期(t1/2=4.1h)、良好的代谢稳定性和较弱的细胞色素P3A4抑制活性，提示18可能是治疗JAK2驱动的骨髓增殖性肿瘤和Flt3内部串联复制驱动的急性髓系白血病的潜在候选药物。
Herein, we describe the design, synthesis, and structure–activity relationships of a series of unique 4-(1H-pyrazol-4-yl)-pyrimidin-2-amine derivatives that selectively inhibit Janus kinase 2 (JAK2) and FLT3 kinases. These screening cascades revealed that18ewas a preferred compound, with IC50values of 0.7 and 4 nM for JAK2 and FLT3, respectively. Moreover,18ewas a potent JAK2 inhibitor with 37-fold and 56-fold selectivity over JAK1 and JAK3, respectively, and possessed an excellent selectivity profile over the other 100 representative kinases. In a series of cytokine-stimulated cell-based assays,18eexhibited a higher JAK2 selectivity over other JAK isoforms. The oral administration of 60 mg/kg of18ecould significantly inhibit tumor growth, with a tumor growth inhibition rate of 93 and 85% in MV4-11 and SET-2 xenograft models, respectively. Additionally,18eshowed an excellent bioavailability (F= 58%), a suitable half-life time (T1/2= 4.1 h), a satisfactory metabolic stability, and a weak CYP3A4 inhibitory activity, suggesting that18emight be a potential drug candidate for JAK2-driven myeloproliferative neoplasms and FLT3-internal tandem duplication-driven acute myelogenous leukemia.