Evaluation of P-1'-diversified phosphinic peptides leads to the development of highly selective inhibitors of MMP-11

• Published in: Journal of medicinal chemistry Vol. 47; no. 2; pp. 325 - 336
• Main Authors: Matziari, M, Beau, F, Cuniasse, P, Dive, Yiotakis, A
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 15.01.2004
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; ACID-DERIVATIVES; DOMAIN; MATRIX-METALLOPROTEINASE INHIBITORS; I-CONVERTING-ENZYME; AMINO-ACIDS; HEART-FAILURE; DRUG DESIGN; STROMELYSIN-3; TRANSITION-STATE; CANCER
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0308491

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 P-1'-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, MMP-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 K-i value of 0.23 PM 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 P-1'-side chain atoms of these inhibitors with residues located at the entrance of the S-1'-cavity of MMP-11. The design of inhibitors able to interact with residues located at the entrance of MMPs' S-1'-cavity might represent an alternative strategy to identify selective inhibitors that will fully differentiate one MMP among the others.