N-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Derivatives as Selective Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms,Journal of Medicinal Chemistry

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N-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Derivatives as Selective Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-30 , DOI: 10.1021/acs.jmedchem.0c01488
Tao Yang ₁ , Mengshi Hu ₁ , Yong Chen ₁ , Mingli Xiang ₁ , Minghai Tang ₁ , Wenyan Qi ₁ , Mingsong Shi ₁ , Jun He ₁ , Xue Yuan ₁ , Chufeng Zhang ₁ , Kongjun Liu ₁ , Jiewen Li ₁ , Zhuang Yang _{1,

2} , Lijuan Chen _{1,

2}

Affiliation

In this study, we described a series of N-(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure–activity relationship though cyclization modification based on previously reported compound 18e led to the discovery of the superior derivative 13ac. Compound 13ac showed excellent potency on JAK2 kinase, SET-2, and Ba/F3^V617F cells (high expression of JAK2^V617F mutation) with IC₅₀ values of 3, 11.7, and 41 nM, respectively. Further mechanistic studies demonstrated that compound 13ac could downregulate the phosphorylation of downstream proteins of JAK2 kinase in cells. Compound 13ac also showed good selectivity in kinase scanning and potent in vivo antitumor efficacy with 82.3% tumor growth inhibition in the SET-2 xenograft model. Moreover, 13ac significantly ameliorated the disease symptoms in a Ba/F3-JAK2^V617F allograft model, with 77.1% normalization of spleen weight, which was more potent than Ruxolitinib.

中文翻译：

N-（嘧啶-2-基）-1,2,3,4-四氢异喹啉-6-胺衍生物作为选择性Janus激酶2抑制剂治疗骨髓增生性肿瘤

在这项研究中，我们描述了一系列的N-（嘧啶-2-基）-1,2,3,4-四氢异喹啉-6-胺衍生物作为选择性JAK2（Janus激酶2）抑制剂。通过基于先前报道的化合物18e的环化修饰，系统地研究结构与活性之间的关系，从而发现了高级衍生物13ac。化合物13ac对JAK2激酶，SET-2和Ba / F3 ^V617F细胞（JAK2 ^V617F突变的高表达）显示出极好的效价，IC ₅₀值分别为3、11.7和41 nM。进一步的机理研究表明，化合物13ac可能下调细胞中JAK2激酶下游蛋白的磷酸化。在SET-2异种移植模型中，化合物13ac在激酶扫描中也显示出良好的选择性，并具有强大的体内抗肿瘤功效，并具有82.3％的肿瘤生长抑制率。此外，13ac显着改善了Ba / F3-JAK2 ^V617F同种异体移植模型的疾病症状，脾脏重量正常化率为77.1％，比鲁索替尼更有效。

更新日期：2020-12-10

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