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Simultaneous Targeting of RGD-Integrins and Dual Murine Double Minute Proteins in Glioblastoma Multiforme

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posted on 18.05.2018, 00:00 by Francesco Merlino, Simona Daniele, Valeria La Pietra, Salvatore Di Maro, Francesco Saverio Di Leva, Diego Brancaccio, Stefano Tomassi, Stefano Giuntini, Linda Cerofolini, Marco Fragai, Claudio Luchinat, Florian Reichart, Chiara Cavallini, Barbara Costa, Rebecca Piccarducci, Sabrina Taliani, Federico Da Settimo, Claudia Martini, Horst Kessler, Ettore Novellino, Luciana Marinelli
In the fight against Glioblastoma Multiforme, recent literature data have highlighted that integrin α5β1 and p53 are part of convergent pathways in the control of glioma apoptosis. This observation prompted us to seek a molecule able to simultaneously modulate both target families. Analyzing the results of a previous virtual screening against murine double minute 2 protein (MDM2), we envisaged that Arg-Gly-Asp (RGD)-mimetic molecules could be inhibitors of MDM2/4. Herein, we present the discovery of compound 7, which inhibits both MDM2/4 and α5β1/αvβ3 integrins. A lead optimization campaign was carried out on 7 with the aim to preserve the activities on integrins while improving those on MDM proteins. Compound 9 turned out to be a potent MDM2/4 and α5β1/αvβ3 blocker. In p53-wild type glioma cells, 9 arrested cell cycle and proliferation and strongly reduced cell invasiveness, emerging as the first molecule of a novel class of integrin/MDM inhibitors, which might be especially useful in subpopulations of patients with glioblastoma expressing a functional p53 concomitantly with a high level of α5β1 integrin.

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