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 IC₅₀ of 0.4 nM with remarkable selectivity (>4300-fold CHK1 vs. CHK2). Compound (R)-17 effectively inhibited the growth of malignant hematopathy cell lines especially Z-138 (IC₅₀: 0.013 μM) and displayed low affinity for hERG (IC₅₀ > 40 μM). Moreover, (R)-17 significantly 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)-17 could be a promising drug candidate for the treatment of hematologic malignancies.

通过虚拟筛选，我们确定了铅化合物MCL1020，该化合物表现出适度的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-基氨基）吡啶甲酸腈衍生物作为CHK1抑制剂。一种有希望的分子，（- [R ）-17，其效力是最好的一个，有一个IC ₅₀为0.4nM的具有显着的选择性（> 4300倍CHK1 VS。CHK2）。化合物（[R ）-17有效抑制恶性血液病细胞系尤其Z-138（IC生长₅₀：0.013  μ M）和显示低亲和力hERG的（IC ₅₀  > 40  μ M）。而且， （R） -17在单一剂量的Z-138细胞接种异种移植模型（20 mg / kg IV，TGI = 90.29％）中显着抑制了肿瘤的生长，而体重没有受到影响。两者合计，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药物。