机构：[1]State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.四川大学华西医院[2]Sichuan Industrial Institute of Antibiotics, Chengdu University , Chengdu 610052, China.[3]Hinova Pharmaceuticals Inc. , Suite 402, Building B, #5 South KeYuan Road, Chengdu, 610041, China.
Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics. A series of dimorpholine substituted thienopyrimidine derivatives had been prepared and evaluated in vitro and in vivo. Among them, compound 14o was identified as a dual Class I PI3K and mTOR kinase inhibitor, which had an approximately 8-fold improvement in mTOR inhibition relative to the class I PI3K inhibitor 1 (pictilisib, GDC-0941). Western blot analysis confirmed the 14o mechanistic modulation of the cellular PI3K/AKT/mTOR pathway through inhibiting phosphorylation of both AKT and S6 in human cancer cell lines. In addition, 14o demonstrated significant efficacy in SKOV-3 and U87MG tumor xenograft models without causing significant weight loss and toxicity.
基金：
National
Natural Science Foundation of China (grants 81472418 and
81672951).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|2 区医学
小类|1 区药物化学
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
共同第一作者：
通讯作者：
通讯机构：[1]State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.[3]Hinova Pharmaceuticals Inc. , Suite 402, Building B, #5 South KeYuan Road, Chengdu, 610041, China.
推荐引用方式(GB/T 7714)：
Zhan Miao,Deng Yufang,Zhao Lifeng,et al.Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors.[J].Journal of medicinal chemistry.2017,60(9):4023-4035.doi:10.1021/acs.jmedchem.7b00357.
APA：
Zhan Miao,Deng Yufang,Zhao Lifeng,Yan Guoyi,Wang Fangying...&Chen Yuanwei.(2017).Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors..Journal of medicinal chemistry,60,(9)
MLA：
Zhan Miao,et al."Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors.".Journal of medicinal chemistry 60..9(2017):4023-4035
医学