Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino) pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies
Discovery of (R)-5-((5-(1-methyl-1H-pyrazol-4-yl)-4-(methylamino) pyrimidin-2-yl)amino)-3-(piperidin-3-yloxy)picolinonitrile, a novel CHK1 inhibitor for hematologic malignancies
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(R)-5-((5-(1-甲基-1H-吡唑-4-基)-4-(甲基氨基)嘧啶-2-基)氨基)-3-(哌啶-3-基氧基)吡啶甲腈的发现
DOI：
10.1016/j.ejmech.2019.03.062
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发表时间：
2019
影响因子：
6.7
通讯作者：
Hu Yongzhou
中科院分区：
文献类型：
--
作者：
Tong Lexian;Song Pinrao;Jiang Kailong;Xu Lei;Jin Tingting;Wang Peipei;Hu Xiaobei;Fang Sui;Gao Anhui;Zhou Yubo;Liu Tao;Li Jia;Hu Yongzhou
通过虚拟筛选，我们确定了先导化合物MCL1020，其表现出适度的CHK1抑制活性。然后通过进一步的合理优化，发现了一系列5-（嘧啶-2-氨基）吡啶腈衍生物作为CHK1抑制剂。(R)-17是一种很有前途的分子，其效价是最好的分子之一，ic50为0.4 nM，具有显著的选择性（bbb4300倍CHK1vs）。相关的)。化合物(R)-17能有效抑制恶性血液病细胞株的生长，特别是Z-138 (IC50: 0.013μM)，对hERG具有较低的亲和力（IC50: > 40μM）。(R)-17单药可显著抑制Z-138 细胞接种异种移植物模型的肿瘤生长（20 mg/kg静脉注射，TGI = 90.29%），且不影响体重。综上所述，我们的数据表明化合物(R)-17可能是治疗血液系统恶性肿瘤的有希望的候选药物。
Through virtual screening, we identified the lead compound MCL1020, which exhibited modest CHK1 inhibitory activity. Then a series of 5-(pyrimidin-2-ylamino)picolinonitrile derivatives as CHK1 inhibitors were discovered by further rational optimization. One promising molecule, (R)-17, whose potency was one of the best, had an IC50of 0.4 nM with remarkable selectivity (>4300-fold CHK1vs. CHK2). Compound (R)-17effectively inhibited the growth of malignant hematopathy cell lines especially Z-138 (IC50: 0.013μM) and displayed low affinity for hERG (IC50> 40μM). Moreover, (R)-17significantly suppressed the tumor growth in Z-138 cell inoculated xenograft model (20 mg/kg I.V., TGI = 90.29%) as a single agent with body weight unaffected. Taken together, our data demonstrated compound (R)-17could be a promising drug candidate for the treatment of hematologic malignancies.