索拉非尼
化学
生物信息学
IC50型
激酶
细胞培养
肝细胞癌
细胞周期
细胞凋亡
生物化学
药理学
体外
癌症研究
生物
基因
遗传学
作者
Anusha Sebastian,Reinad R. Abu Rabah,Seyed–Omar Zaraei,Vunnam Srinivasulu,Shaista Sultan,Hanan S. Anbar,Randa El-Gamal,Hamadeh Tarazi,Nadin H. Sarg,Dima W. Alhamad,Salma A. Al Shamma,Afnan I. Shahin,Hany A. Omar,Taleb H. Al‐Tel,Mohammed I. El‐Gamal
标识
DOI:10.1016/j.ejmech.2024.116557
摘要
Herein, we report on the discovery of novel 4-carboxamidopyrido[3,2-b]pyridine derivatives that showed potent antiproliferative activities against a panel of NCI-60 cancer cell lines as well as hepatocellular carcinoma cell line. Compounds 8g and 9f were among the most promising compounds in terms of effectiveness and safety. Therefore, they were further examined to demonstrate their ability to induce apoptosis and alter cell cycle progression in hepatocellular carcinoma cells. The most potent compounds were tested against a panel of kinases that indicated their selectivity against FMS kinase. Compounds 8g and 8h showed the most potent activities against FMS kinase with IC50 values of 21.5 and 73.9 nM, respectively. The two compounds were also tested in NanoBRET assay to investigate their ability to inhibit FMS kinase in cells (IC50 = 563 nM (8g) and 1347 nM (8h) vs. IC50 = 1654 nM for sorafenib). Furthermore, compounds 8g and 8h possess potent inhibitory activities of macrophages when investigated in bone marrow-derived macrophages (BMDM) assay (IC50 = 56 nM and 167 nM, respectively, 164 nM for sorafenib). These compounds indicated their safety and selectivity when tested against normal cell lines. Their safety profile was further confirmed using hERG assay. In silico studies were carried out to investigate their binding modes in the active site of FMS kinase, and to develop a QSAR model for these new motifs.
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