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 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.
Department of Chemistry, Renmin University of China, Beijing 100872, China. zilichen@ruc.edu.cn.
Xiaoxiao
X
Li
Jianjun
J
Hou
Chao
C
Wang
Xinjie
X
Liu
Hongyan
H
He
Ping
P
Xu
Zhenjun
Z
Yang
Zili
Z
Chen
Yun
Y
Wu
Lihe
L
Zhang
D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
D001549:Benzamides; D039302:Integrin alphaVbeta3; D016023:Integrins; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; C047981:arginyl-glycyl-aspartic acid; C506614:mirdametinib; D004159:Diphenylamine; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2