结直肠癌
化学
体内
癌症
酶
癌症研究
细胞培养
IC50型
细胞生长
泛素
生物化学
体外
药理学
生物
基因
内科学
医学
生物技术
遗传学
作者
Xueyuan Wang,Tiantian Wen,Hang Miao,Wenjiao Hu,Lei Meng,Yongqiang Zhu
标识
DOI:10.1016/j.bmc.2022.117050
摘要
Colorectal cancer (CRC) is a common digestive tract malignant tumor and is the third cancer-related death worldwide. Valosine containing protein (VCP/p97) is a member of the AAA ATPase family, plays an important role in the ubiquitin-mediated degradation of misfolded proteins. Studies have shown that p97 is overexpressed in colorectal cancer and is a potential therapeutic target. Herein, a series of novel p97 inhibitors were designed, synthesized and biologically assayed. Based on the enzymatic results, structure-activity relationships (SAR) were discussed in detail. Some potent compounds were further evaluated to inhibit the proliferation of CRC cell lines HCT-116. The results showed that some compounds were active against CRC cell lines with IC50 values of less than 1 μM. Among the screened compounds, compound 10 exhibited good microsomal stabilities, pharmacokinetic properties and displayed strong antiproliferative activity against the HCT-116 cell line (0.4 μM). Furthermore, compound 10 exhibited strong in vivo anticancer efficacy in the human CRC (HCT-116) mouse xenograft model.
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