European Journal of Medicinal Chemistry p. 44 - 62 (2019)
Update date:2022-08-03
Topics:
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
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.
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