Molecules 2013, 18(11), 13957-13978; doi:10.3390/molecules181113957
Article

Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy

1 Department of Chemistry, Renmin University of China, Beijing 100872, China 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
* Authors to whom correspondence should be addressed.
Received: 27 September 2013; in revised form: 12 October 2013 / Accepted: 15 October 2013 / Published: 12 November 2013
(This article belongs to the Section Medicinal Chemistry)
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Abstract: 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 9ag 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.
Keywords: RGD-MEKI conjugate; MEK1/2 kinase inhibitor; PD0325901; RGD peptide; integrin αvβ3 receptor; tumor-targeted drug delivery

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MDPI and ACS Style

Li, X.; Hou, J.; Wang, C.; Liu, X.; He, H.; Xu, P.; Yang, Z.; Chen, Z.; Wu, Y.; Zhang, L. Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy. Molecules 2013, 18, 13957-13978.

AMA Style

Li X, Hou J, Wang C, Liu X, He H, Xu P, Yang Z, Chen Z, Wu Y, Zhang L. Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy. Molecules. 2013; 18(11):13957-13978.

Chicago/Turabian Style

Li, Xiaoxiao; Hou, Jianjun; Wang, Chao; Liu, Xinjie; He, Hongyan; Xu, Ping; Yang, Zhenjun; Chen, Zili; Wu, Yun; Zhang, Lihe. 2013. "Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy." Molecules 18, no. 11: 13957-13978.

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