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学科主题: 药学
题名:
Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy
作者: 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
发表日期: 2013-11-01
DOI: 10.3390/molecules181113957
卷: 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
所属项目编号: 20120001120023 ; 2009ZX09301-010 ; 21072224 ; 21272268 ; 11XNI003
项目资助者: 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
WOS记录号: WOS:000330311500056
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/63608
Appears in Collections:北京大学药学院_期刊论文

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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

Recommended Citation:
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.
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