Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy
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 mechani...
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Online Access: | http://www.mdpi.com/1420-3049/18/11/13957 |
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doaj-1895603840ca4f86a26953272fe4efbe2020-11-24T21:26:11ZengMDPI AGMolecules1420-30492013-11-011811139571397810.3390/molecules181113957Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer TherapyYun WuZili ChenZhenjun YangPing XuHongyan HeXinjie LiuChao WangXiaoxiao LiJianjun HouLihe ZhangTwo 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.http://www.mdpi.com/1420-3049/18/11/13957RGD-MEKI conjugateMEK1/2 kinase inhibitorPD0325901RGD peptideintegrin αvβ3 receptortumor-targeted drug delivery |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yun Wu Zili Chen Zhenjun Yang Ping Xu Hongyan He Xinjie Liu Chao Wang Xiaoxiao Li Jianjun Hou Lihe Zhang |
spellingShingle |
Yun Wu Zili Chen Zhenjun Yang Ping Xu Hongyan He Xinjie Liu Chao Wang Xiaoxiao Li Jianjun Hou Lihe Zhang Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy Molecules RGD-MEKI conjugate MEK1/2 kinase inhibitor PD0325901 RGD peptide integrin αvβ3 receptor tumor-targeted drug delivery |
author_facet |
Yun Wu Zili Chen Zhenjun Yang Ping Xu Hongyan He Xinjie Liu Chao Wang Xiaoxiao Li Jianjun Hou Lihe Zhang |
author_sort |
Yun Wu |
title |
Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy |
title_short |
Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy |
title_full |
Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy |
title_fullStr |
Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy |
title_full_unstemmed |
Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy |
title_sort |
synthesis and biological evaluation of rgd-conjugated mek1/2 kinase inhibitors for integrin-targeted cancer therapy |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2013-11-01 |
description |
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. |
topic |
RGD-MEKI conjugate MEK1/2 kinase inhibitor PD0325901 RGD peptide integrin αvβ3 receptor tumor-targeted drug delivery |
url |
http://www.mdpi.com/1420-3049/18/11/13957 |
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