Evaluation of P1'-diversified phosphinic peptides leads to the development of highly selective inhibitors of MMP-11

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.