Zhan Wenhu, Xu Lei, Dong Xiaowu, Dong Jun, Yi Xiao, Ma Xiaodong, Qiu Ni, Li Jia, Yang Bo, Zhou Yubo, Hu Yongzhou
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Eur J Med Chem. 2016 Jul 19;117:47-58. doi: 10.1016/j.ejmech.2016.03.074. Epub 2016 Apr 5.
A series of novel pyrazol-furan carboxamide analogues were designed, synthesized and biologically evaluated for their Akt1 inhibitory activities, as well as anti-proliferative efficacies against HCT116 and OVCAR-8 cell lines. Most compounds exhibited moderate to excellent Akt1 inhibitory activities, together with favorable cytotoxicities. Further kinase selectivity assay of the most promising compound 25e illustrated that it was also potent against the structurally related AGC kinases, including Akt2, Akt3, ROCK1 and PKA, but was specific over kinases from other subfamilies. In addition, the Western blot analysis indicated that 25e could significantly suppress the phosphorylation level of Akt substrate GSK3β in PC-3 cell. Moreover, 25e demonstrated a concentration-dependent inhibition of phosphorylation of PRAS40 in LNCaP cell, with IC50 value of 30.4 nM.
设计、合成了一系列新型吡唑 - 呋喃甲酰胺类似物，并对其Akt1抑制活性以及对HCT116和OVCAR - 8细胞系的抗增殖功效进行了生物学评估。大多数化合物表现出中等至优异的Akt1抑制活性以及良好的细胞毒性。对最有前景的化合物25e进行的进一步激酶选择性测定表明，它对结构相关的AGC激酶（包括Akt2、Akt3、ROCK1和PKA）也有强效作用，但对其他亚家族的激酶具有特异性。此外，蛋白质印迹分析表明，25e可显著抑制PC - 3细胞中Akt底物GSK3β的磷酸化水平。此外，25e在LNCaP细胞中表现出对PRAS40磷酸化的浓度依赖性抑制，IC50值为30.4 nM。
