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.

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

NUTI, ELISA
Primo
;
CUFFARO, DORETTA;CAMODECA, CATERINA;GIACOMELLI, CHIARA;DA POZZO, ELEONORA;TUCCINARDI, TIZIANO;COSTA, BARBARA;CICCONE, LIDIA;ORLANDINI, ELISABETTA;NENCETTI, SUSANNA;MARTINI, CLAUDIA;ROSSELLO, ARMANDO
2017-01-01

Abstract

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.
2017
Nuti, Elisa; Rosalia, Lea; Cuffaro, Doretta; Camodeca, Caterina; Giacomelli, Chiara; DA POZZO, Eleonora; Tuccinardi, Tiziano; Costa, Barbara; Antoni, ...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/850358
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