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

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.