化学
支票1
激酶
酶抑制剂
组合化学
立体化学
药理学
体外
生物化学
细胞周期检查点
细胞周期
细胞凋亡
医学
作者
Shihe Hu,Cuihua Jiang,Qiaomei Jin
标识
DOI:10.1016/j.ejmech.2024.116351
摘要
Checkpoint kinase 1 (CHK1) plays a crucial role in the DNA damage response pathway, making it an attractive target for cancer therapy. Herein, we present the synthesis, optimization, and evaluation of selective CHK1 inhibitors with a pyrido[3,2-d]pyrimidin-6(5H)-one scaffold. Among them, compound 11 showed single-digit nanomolar potency against CHK1 (IC50: 0.55 nM) with good kinase selectivity. Notably, 11 showed anti-proliferative effect in MV-4-11 cells singly (IC50 = 202 nM) and a synergistic effect in combination with gemcitabine in HT-29 cells (IC50 = 63.53 nM). Furthermore, the combination of 11 and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Overall, this work provides a strong foundation for the development of selective CHK1 inhibitors and the therapeutic strategy for cancer.
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