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Discovery of novel ceramide analogs with favorable pharmacokinetic properties and combination with AKT inhibitor against colon cancer

文献类型：期刊论文

作者Gao, Feng1,2,3; Chen, Xiaoxu1,2,3,4; Lu, Junyan1,2,3; Hu, Shulei1,2,3; Xu, Hui1,2,3; Shi, Yuqiang1,2,3; Feng, Mingshun1,2,4; Ding, Jian1,2,3,4; Liu, Hong1,2,3,4; Luo, Cheng1,2,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-04-05
卷号215页码:13
ISSN号0223-5234
关键词Ceramide analogs AKT inhibitor MK2206 Colon cancer Combination therapy
DOI10.1016/j.ejmech.2021.113274
通讯作者Luo, Cheng(cluo@simm.ac.cn) ; Xie, Zuoquan(zqxie@simm.ac.cn) ; Wang, Jiang(jwang@simm.ac.cn)
英文摘要Ceramides have emerged as potential therapeutic option with novel mechanism to affect the proliferation, differentiation, senescence, and apoptosis of cancer cells through regulation of multiple signal transduction. Aiming at the improvement of the apoptosis activity and pharmacokinetic profiles of ceramides, a novel series of ceramide analogs were developed through structure simplification and conformation restriction. Among them, compound 12 bearing an alkoxyl naphthyl motif, with favorable rat pharmacokinetic properties, showed better anti-proliferative activity against various colon cancer cells (IC50 similar to 20 mM) than other ceramide analogues, as well as the synergistic effect combined with AKT inhibitor MK2206. Additionally, we demonstrated that this combination therapy promoted caspase 3-dependent apoptotic pathway and intensified cell cycle arrest in the G0/G1 phase. Furthermore, the combination of compound 12 and MK2206 displayed synergistic anti-tumor effect in vivo. (c) 2021 Published by Elsevier Masson SAS.
资助项目National Natural Science Foundation of China[91953108] ; National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[21877118] ; Personalized Medicinesdd-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020341] ; Shanghai Pujiang Program[18PJD052]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:000634820600021
源URL[http://119.78.100.183/handle/2S10ELR8/295259]  
专题新药研究国家重点实验室
通讯作者Luo, Cheng; Xie, Zuoquan; Wang, Jiang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
推荐引用方式
GB/T 7714		 Gao, Feng,Chen, Xiaoxu,Lu, Junyan,et al. Discovery of novel ceramide analogs with favorable pharmacokinetic properties and combination with AKT inhibitor against colon cancer[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,215:13.
APA Gao, Feng.,Chen, Xiaoxu.,Lu, Junyan.,Hu, Shulei.,Xu, Hui.,...&Wang, Jiang.(2021).Discovery of novel ceramide analogs with favorable pharmacokinetic properties and combination with AKT inhibitor against colon cancer.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,215,13.
MLA Gao, Feng,et al."Discovery of novel ceramide analogs with favorable pharmacokinetic properties and combination with AKT inhibitor against colon cancer".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 215(2021):13.

入库方式： OAI收割

来源：上海药物研究所

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