Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia
Design, Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia
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口服生物可利用的 CHK1 抑制剂的设计、合成和生物学评价对急性髓系白血病有活性
DOI：
10.1002/cmdc.202000882
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发表时间：
2021-02
期刊：
影响因子：
3.4
通讯作者：
Tao Liu
中科院分区：
文献类型：
--
作者：
Tingting Jin;Peipei Wang;Xiubing Long;Kailong Jiang;Pinrao Song;Wenbiao Wu;Gaoya Xu;Yubo Zhou;Jia Li;Tao Liu
检查点激酶 1 (CHK1) 是 DNA 损伤反应的核心成分，已成为抗肿瘤治疗的靶点。在此，我们描述了一系列新型强效二氨基嘧啶 CHK1 抑制剂的设计、合成和生物学评价。这些化合物表现出中度至强效的 CHK1 抑制作用，并能抑制恶性血液细胞系的增殖。优化后的化合物13的CHK1 IC50值为7.73±0.74 nM，MV-4-11细胞对其敏感（IC50=0.035±0.007 μM）。此外，化合物 13 在体外小鼠肝微粒体中代谢稳定，并在体内表现出中等的口服生物利用度。此外，用化合物 13 处理 MV-4-11 细胞 2 h，可强烈抑制丝氨酸 296 上的 CHK1 自磷酸化。基于这些生化结果，我们认为化合物 13 是一种有前途的 CHK1 抑制剂和潜在的抗癌治疗剂。
Checkpoint kinase 1 (CHK1) is a central component in DNA damage response and has emerged as a target for antitumor therapeutics. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent diaminopyrimidine CHK1 inhibitors. The compounds exhibited moderate to potent CHK1 inhibition and could suppress the proliferation of malignant hematological cell lines. The optimized compound 13 had a CHK1 IC50 value of 7.73±0.74 nM, and MV‐4‐11 cells were sensitive to it (IC50=0.035±0.007 μM). Furthermore, compound 13 was metabolically stable in mouse liver microsomes in vitro and displayed moderate oral bioavailability in vivo. Moreover, treatment of MV‐4‐11 cells with compound 13 for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Based on these biochemical results, we consider compound 13 to be a promising CHK1 inhibitor and potential anticancer therapeutic agent.