Bifunctional Inhibitors as a New Tool To Reduce Cancer Cell Invasion by Impairing MMP-9 Homodimerization.

Autor:	Nuti E; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Rosalia L; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Cuffaro D; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Camodeca C; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Giacomelli C; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Da Pozzo E; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Tuccinardi T; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Costa B; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Antoni C; Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy; CEA, iBiTec-S, Service d'Ingenierie Moleculaire des Proteines, CE-Saclay, 91191 Gif sur Yvette Cedex, France., Vera L; CEA, iBiTec-S , Service d'Ingenierie Moleculaire des Proteines, CE-Saclay, 91191 Gif sur Yvette Cedex, France., Ciccone L; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Orlandini E; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Nencetti S; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Dive V; CEA, iBiTec-S , Service d'Ingenierie Moleculaire des Proteines, CE-Saclay, 91191 Gif sur Yvette Cedex, France., Martini C; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy., Stura EA; CEA, iBiTec-S , Service d'Ingenierie Moleculaire des Proteines, CE-Saclay, 91191 Gif sur Yvette Cedex, France., Rossello A; Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2017 Feb 07; Vol. 8 (3), pp. 293-298. Date of Electronic Publication: 2017 Feb 07 (Print Publication: 2017).
DOI:	10.1021/acsmedchemlett.6b00446
Abstrakt:	Protein homodimers play important roles in physiological and pathological processes, including cancer invasion and metastasis. Recently, MMP-9 natural homodimerization via the PEX domain has been correlated with high migration rates of aggressive cancer cells. Here we propose that bifunctional MMP-9 inhibitors designed to impair natural MMP-9 homodimerization promoted by PEX-PEX interactions might be an effective tool to fight cancer cell invasion. Elaborating a previously described dimeric hydroxamate inhibitor 1 , new ligands were synthesized with different linker lengths and branch points. Evaluation of the modified bifunctional ligands by X-ray crystallography and biological assays showed that 7 and 8 could reduce invasion in three glioma cell lines expressing MMP-9 at different levels. To rationalize these results, we present a theoretical model of full-length MMP-9 in complex with 7 . This pioneering study suggests that a new approach using MMP-9 selective bifunctional inhibitors might lead to an effective therapy to reduce cancer cell invasion.
Databáze:	MEDLINE
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