Evaluation of P1'-Diversified Phosphinic Peptides Leads to the Development of Highly Selective Inhibitors of MMP-11

Magdalini Matziari, Fabrice Beau, Philippe Cuniasse, Vincent Dive, Athanasios Yiotakis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

Phosphinic peptides were previously reported to be potent inhibitors of several matrixins (MMPs). To identify more selective inhibitors of MMP-11, a matrixin overexpressed in breast cancer, a series of phosphinic pseudopeptides bearing a variety of P1'-side chains has been synthesized, by parallel diversification of a phosphinic template. The potencies of these compounds were evaluated against a set of seven MMPs (MMP-2, MMP-7, MP-8, MMP-9, MMP-11, MMP-13, and MMP-14). The chemical strategy applied led to the identification of several phosphinic inhibitors displaying high selectivity toward MMP-11. One of the most selective inhibitors of MMP-11 in this series, compound 22, exhibits a Ki value of 0.23 μM toward MMP-11, while its potency toward the other MMPs tested is 2 orders of magnitude lower. This remarkable selectivity may rely on interactions of the P1'-side chain atoms of these inhibitors with residues located at the entrance of the S1'-cavity of MMP-11. The design of inhibitors able to interact with residues located at the entrance of MMPs' S1'-cavity might represent an alternative strategy to identify selective inhibitors that will fully differentiate one MMP among the others.

Original languageEnglish
Pages (from-to)325-336
Number of pages12
JournalJournal of Medicinal Chemistry
Volume47
Issue number2
DOIs
Publication statusPublished - 15 Jan 2004
Externally publishedYes

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