药效团
HDAC1型
化学
双功能
IC50型
效力
激酶
免疫印迹
磷酸化
C-Met公司
药理学
组蛋白脱乙酰基酶
生物化学
体外
生物
组蛋白
受体
肝细胞生长因子
催化作用
基因
作者
Dong Lu,Juan Yan,Lang Wang,Hongchun Liu,Limin Zeng,Minmin Zhang,Wenwen Duan,Yinchun Ji,Jingchen Cao,Meiyu Geng,Aijun Shen,Youhong Hu
标识
DOI:10.1021/acsmedchemlett.7b00172
摘要
Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, 2m, inhibited c-Met kinase and HDAC1, with IC50 values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide. Western blot analysis revealed that compound 2m inhibited phosphorylation of c-Met and c-Met downstream signaling proteins and increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent manner. Our study presents novel compounds for the further exploration of dual c-Met/HDAC pathway inhibition achieved with a single molecule.
科研通智能强力驱动
Strongly Powered by AbleSci AI