化学
克拉斯
咪唑
激酶
IC50型
立体化学
体外
癌症研究
药理学
生物化学
突变
生物
基因
作者
Peng Wang,Yong Yuan,Tao Yang,Yurong Zou,Minghai Tang,Ziyan Ma,Weichen Bo,Songhui Qin,Yong Chen,Tao Guo,Zhixing Guo,Jianhong Yang,Mingli Xiang,Lijuan Chen
标识
DOI:10.1021/acs.jmedchem.4c00860
摘要
Herein, we described the rational drug design and synthesis of a series of 5-amino-4-fluoro-1H-benzo[d]imidazole-6-carboxamide derivatives that inhibit MEK and RAF kinases. The detailed screening cascades revealed that 16b was a preferred compound, which might act like a "clamp" to stabilize the MEK/RAF complex, thereby effectively inhibiting MEK1, BRAF, and BRAFV600E with IC50 values of 28, 3, and 3 nM, respectively. 16b possessed an excellent selectivity over other 312 human-related kinases at 1 μM. In vitro, 16b showed potent antiproliferative activities against MIA PaCa-2 (G12C KRAS), HCT116 (G13D KRAS), and C26 (G12D KRAS) cells with IC50 values of 0.011, 0.079, and 0.096 μM, respectively. CoIP experiments demonstrated that 16b could induce MEK/RAF complex formation. Most importantly, in the C26 syngeneic colorectal and HCT116 mice xenograft tumor models, 16b demonstrated tumor growth inhibition of 70 and 93%, respectively, suggesting that 16b may be a promising MEK/RAF complex inhibitor and worthy of further development.
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