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

Abstract

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.

The functional role of integrins during intra- and extravasation within the metastatic cascade

“…It seems plausible that the inhibition of a single integrin may not suppress the complete adhesive cell function in a cell that expresses a pattern of different integrins. Apart from dual and multi-integrin inhibitors, the combination of integrin antagonists with other drugs with anti-tumor activity such as chemotherapeutics are being evaluated [142, 148]. An integrin inhibitor could intensify and reinforce the anti-tumor effect of an oncologic treatment, rather than be used as a single-agent.…”

Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer

“…MDM2based multi-target inhibitors could improve the efficacy and reduce the side effects (de Lera and Ganesan, 2016). Dual inhibitors that have been reported to be co-inhibit with MDM2 include MDM4, NF-kB, histone deacetylases (HDAC), translocator protein (TSPO), XIAP, and integrins (McCormack et al, 2012;Daniele et al, 2016;Gu et al, 2016;Shirai et al, 2016;Giustiniano et al, 2017;Merlino et al, 2018), which achieved excellent in vitro and in vivo antitumor potency. Considering MDM2 and MDM4 dual inhibitors had been well reviewed in the recent literature (Teveroni et al, 2016;Espadinha et al, 2018), we summarize other dual inhibitors.…”

“…An effective a5b1/avb3 integrin binding agent was identified to inhibit MDM2/4 activity and reactivated p53 pathway. In addition, this compound can induce cell cycle arrest, reduce the invasiveness of GBM cells and block the proliferation of p53 wild-type GBM cells (Merlino et al, 2018). The novel class of integrin/MDM2 inhibitors is useful in the subpopulation of patients with glioblastoma expressing functional p53 concomitantly with a high level of a5b1 integrin (Merlino et al, 2018).…”

A Novel Small Molecule p53 Stabilizer for Brain Cell Differentiation

“…This, in turn, could be achieved by reactivating endogenous differentiation programs in cancer cells to resume the maturation process and eliminate tumor phenotypes. In this regard, recent reports have highlighted the importance of p53 tumor suppressor in controlling stem cell fate and glioma cell proliferation and invasiveness (Qin et al, 2007; Molchadsky et al, 2010; Zhao and Xu, 2010; Li et al, 2013; Merlino et al, 2018). The first indication that p53 could inhibit neural stem cells (NSCs) self-renewal was observed in p53 knockout mice, in which increased levels of cell self-renewal were detected in the neurogenic niches, when compared with wild-type animals (Meletis et al, 2006).…”