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 microM 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.
Matziari
Magdalini
M
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis Zografou 15771, Athens, Greece.
Beau
Fabrice
F
Cuniasse
Philippe
P
Dive
Vincent
V
Yiotakis
Athanasios
A
D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C482217:(1-benzyloxycarbonylamino-2-phenylethyl)-(2-(1-carbamoyl-2-(1H-indol-3-yl)ethylcarbamoyl)-3-(2-methoxyphenylsulfanyl)propyl)phosphinic acid; D007211:Indoles; D010455:Peptides; D010721:Phosphinic Acids; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases