化学
伊立替康
羧酸酯酶
IC50型
体内
前药
药理学
MTT法
对接(动物)
毒性
腹泻
体外
酶
立体化学
生物化学
结直肠癌
癌症
生物
医学
遗传学
生物技术
护理部
有机化学
内科学
作者
Zhongcheng Yang,Zhijun Cao,Wenxin Wang,Ya Chen,Wanqiu Huang,Shixuan Jiao,Siliang Chen,Lianru Chen,Yuxia Liu,Jianming Mao,Luyong Zhang,Zheng Li
标识
DOI:10.1016/j.bioorg.2023.106625
摘要
Human carboxylesterase 2 (hCES2A), one of the most important serine hydrolases distributed in the small intestine and colon, plays a crucial role in the hydrolysis of various prodrugs and esters. Accumulating evidence has demonstrated that the inhibition of hCES2A effectively alleviate the side effects induced by some hCES2A-substrate drugs, including delayed diarrhea caused by the anticancer drug irinotecan. Nonetheless, there is a scarcity of selective and effective inhibitors that are suitable for irinotecan-induced delayed diarrhea. Following screening of the in-house library, the lead compound 01 was identified with potent inhibition on hCES2A, which was further optimized to obtain LK-44 with potent inhibitory activity (IC50 = 5.02 ± 0.67 μM) and high selectivity on hCES2A. Molecular docking and molecular dynamics simulations indicated that LK-44 can formed stable hydrogen bonds with amino acids surrounding the active cavity of hCES2A. The results of inhibition kinetics studies unveiled that LK-44 inhibited hCES2A-mediated FD hydrolysis in a mixed inhibition manner, with a Ki value of 5.28 μM. Notably, LK-44 exhibited low toxicity towards HepG2 cells according to the MTT assay. Importantly, in vivo studies showed that LK-44 significantly reduced the side effects of irinotecan-induced diarrhea. These findings suggested that LK-44 is a potent inhibitor of hCES2A with high selectivity against hCES1A, which has potential as a lead compound for the development of more effective hCES2A inhibitors to mitigate irinotecan-induced delayed diarrhea.
科研通智能强力驱动
Strongly Powered by AbleSci AI