期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 215, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113288
关键词
S-Trityl-(L)-cysteine; Kinesin spindle protein; Inhibitor; Molecular dynamics simulation; gamma-glutamyltransferase; Prodrug
资金
- Drug Discovery Program of the Pharma Valley Center
- JSPS KAKENHI [17K08366, 20K06969]
- Grants-in-Aid for Scientific Research [20K06969, 17K08366] Funding Source: KAKEN
The researchers optimized the design of KSP inhibitors through computational modeling and developed a prodrug compound that could be hydrolyzed by GGT to produce an inhibitor with KSP ATPase inhibitory activity and demonstrated higher selectivity toxicity in GGT-expressing cancer cells.
Kinesin spindle protein (KSP) is expressed only in cells undergoing cell division, and hence represents an attractive target for the treatment of cancer. Several KSP inhibitors have been developed and undergone clinical trial, but their clinical use is limited by their toxicity to rapidly proliferating non-cancerous cells. To create new KSP inhibitors that are highly selective for cancer cells, we optimized the amino acid moiety of S-trityl-(L)-cysteine (STLC) derivative 1 using in silico modeling. Molecular docking and molecular dynamics simulation were performed to investigate the binding mode of 1 with KSP. Consistent with the structure activity relationship studies, we found that a cysteine amino moiety plays an important role in stabilizing the interaction. Based on these findings and the structure of GSH, a substrate of gamma-glutamyltransferase (GGT), we designed and synthesized the prodrug N-gamma-glutamylated STLC derivative 9, which could be hydrolyzed by GGT to produce 1. The KSP ATPase inhibitory activity of 9 was lower than that of 1, and LC-MS analysis indicated that 9 was converted to 1 only in the presence of GGT in vitro. In addition, the cytotoxic activity of 9 was significantly attenuated in GGT-knockdown A549 cells. Since GGT is overexpressed on the cell membrane of various cancer cells, these results suggest that compound 9 could be a promising prodrug that selectively inhibits the proliferation of GGT-expressing cancer cells. (c) 2021 Elsevier Masson SAS. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据