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

Journal of Medicinal Chemistry
Francesco MerlinoLuciana Marinelli

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.

References

Jul 22, 1998·Nucleic Acids Research·J MomandJ Niland
Aug 17, 1999·Journal of Medicinal Chemistry·M A DechantsreiterH Kessler
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Aug 6, 2004·Journal of Medicinal Chemistry·Luciana MarinelliHorst Kessler
Sep 14, 2004·Journal of Combinatorial Chemistry·Francesca GagginiMaurizio Taddei
Jun 15, 2005·Journal of Molecular Biology·Stanislava UhrinovaPaul N Barlow
Sep 15, 2005·The Journal of Biological Chemistry·Seung-Wook ChiKyou-Hoon Han
Aug 15, 2006·The Journal of Biological Chemistry·Baoli HuJiandong Chen
Aug 15, 2006·The Journal of Biological Chemistry·Mark WadeGeoffrey M Wahl
Nov 2, 2007·Journal of Medicinal Chemistry·Jayanta ChatterjeeHorst Kessler
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Nov 26, 2009·Nature Reviews. Cancer·Christopher J BrownDavid P Lane
Dec 24, 2009·Nature Reviews. Cancer·Jay S Desgrosellier, David A Cheresh
Jan 19, 2010·The Journal of Biological Chemistry·Damon ReedMichael A Dyer
Jan 26, 2010·International Journal of Cancer. Journal International Du Cancer·Eva MartinkovaMonique Dontenwill
Nov 16, 2010·Cancer Cell·Federico BernalLoren D Walensky
Jan 29, 2011·Anti-cancer Agents in Medicinal Chemistry·Carlos Mas-MorunoHorst Kessler
Feb 16, 2011·Journal of Medicinal Chemistry·Stefania ButiniFederico Focher
Mar 2, 2011·Anti-cancer Agents in Medicinal Chemistry·Vita M Golubovskaya, William G Cance
Sep 13, 2011·Journal of Medicinal Chemistry·Oliver DemmerHorst Kessler
Sep 29, 2011·Angewandte Chemie·Carlos Mas-MorunoHorst Kessler
Jan 11, 2013·Nature Reviews. Cancer·Mark WadeGeoffrey M Wahl
Aug 27, 2013·PloS One·Barbara CostaClaudia Martini
Mar 1, 2014·Nature Reviews. Drug Discovery·Kian Hoe KhooDavid P Lane
Mar 25, 2014·Journal of Medicinal Chemistry·Stefanie NeubauerHorst Kessler
Mar 25, 2014·Nature Structural & Molecular Biology·Johannes F Van AgthovenM Amin Arnaout

❮ Previous
Next ❯

Citations

Jan 19, 2019·Molecular Cancer·Greta Sökeland, Udo Schumacher
Feb 16, 2019·Frontiers in Chemistry·Joana D AmaralMaria M M Santos
May 14, 2019·International Journal of Oncology·Iris Maria ForteAntonio Giordano
Feb 14, 2021·European Journal of Pharmacology·Simona DanieleLuciana Marinelli
Jul 27, 2021·Frontiers in Oncology·Xanthene MilesJulie Bolcaen

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Adhesion Molecules in Health and Disease

Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.