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Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy
Li, Xiaoxiao1; Hou, Jianjun2; Wang, Chao2; Liu, Xinjie2; He, Hongyan2; Xu, Ping2; Yang, Zhenjun2; Chen, Zili1; Wu, Yun2; Zhang, Lihe2
关键词RGD-MEKI conjugate MEK1/2 kinase inhibitor PD0325901 RGD peptide integrin alpha(v)beta(3) receptor tumor-targeted drug delivery
刊名MOLECULES
2013-11-01
DOI10.3390/molecules181113957
18期:11页:13957-13978
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Organic
研究领域[WOS]Chemistry
关键词[WOS]PHASE-I ; ALPHA(V)BETA(3) EXPRESSION ; PATHWAY ; DERIVATIVES ; PD-0325901 ; PEPTIDE ; ANALOGS ; CI-1040 ; GROWTH ; VITRO
英文摘要

Two novel series of RGD-MEKI conjugates derived from a MEK1/2 kinase inhibitor-PD0325901-have been developed for integrin receptor mediated anticancer therapy. The first series, alkoxylamine analog RGD-MEKI conjugates 9a-g showed anti-proliferation activity in melanoma A375 cells by the same mechanism as that of PD0325901. PEGylation increased the IC50 value of 9f three-fold in the A375 assay, and the multi-cRGD peptide cargo significantly improved the receptor specific anti-proliferation activity of 9g in integrin-overexpressing U87 cells. In the second series, RGD-PD0325901 13 exhibited significantly increased antitumor properties compared to the alkoxylamine analogs by both inhibition of the ERK pathway activity and DNA replication of the cancer cells. Furthermore, 13 displayed more potent anti-proliferation activity in the U87 assay than PD0325901 in a dose-dependent manner. All these data demonstrate that RGD-MEKI conjugates with an ester bond linkage enhanced anticancer efficacy with improved targeting capability toward integrin-overexpressing tumor cells.

语种英语
WOS记录号WOS:000330311500056
项目编号20120001120023 ; 2009ZX09301-010 ; 21072224 ; 21272268 ; 11XNI003
资助机构Specialized Research Fund for the Doctoral Program of Higher Education ; Ministry of Science and Technology of China ; National Sciences Foundation of China ; Fundamental Research Funds for the Central Universities ; Research Funds of Renmin University of China
引用统计
被引频次:7[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/63608
专题北京大学药学院
北京大学药学院_药物化学系
北京大学第二临床医学院_消化科
作者单位1.Renmin Univ China, Dept Chem, Beijing 100872, Peoples R China
2.Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
推荐引用方式
GB/T 7714
Li, Xiaoxiao,Hou, Jianjun,Wang, Chao,et al. Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy[J]. MOLECULES,2013,18(11):13957-13978.
APA Li, Xiaoxiao.,Hou, Jianjun.,Wang, Chao.,Liu, Xinjie.,He, Hongyan.,...&Zhang, Lihe.(2013).Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy.MOLECULES,18(11),13957-13978.
MLA Li, Xiaoxiao,et al."Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy".MOLECULES 18.11(2013):13957-13978.
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