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Discovery of a d-pro-lys peptidomimetic inhibitor of MMP9: Addressing the gelatinase selectivity beyond S1' subsite.

Authors
  • Lenci, Elena1
  • Contini, Alessandro2
  • Trabocchi, Andrea3
  • 1 Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: [email protected] , (Italy)
  • 2 Department of Pharmaceutical Sciences, University of Milan, Via Venezian 21, I-20133 Milan, Italy. , (Italy)
  • 3 Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy; Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Viale Morgagni 85, 50134 Florence, Italy. Electronic address: [email protected] , (Italy)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Aug 05, 2020
Volume
30
Issue
20
Pages
127467–127467
Identifiers
DOI: 10.1016/j.bmcl.2020.127467
PMID: 32768649
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Despite a high degree of structural similarity, it is known that MMP2 and MMP9 have distinct roles in the angiogenic switch and in cell migration, as they activate diverse signaling pathways. Indeed, inhibition of MMP2 and MMP9 can show beneficial or detrimental effects depending on the stage of tumor progression. Thus, the selective inhibition of gelatinases is of relevance for a successful drug lead, which has to be achieved despite the high structural similarity of the two gelatinases. Herein, the synthesis and evaluation of d-proline-derived hydroxamic acids containing amino appendages at C-4 as gelatinase inhibitors are reported. Inhibition assays enabled the identification of a > 200-fold selective MMP9 inhibitor when Lys was considered as a C-4 substituent, thus addressing gelatinase selectivity beyond the S1' subsite, which is a major driver for selectivity. Molecular docking studies revealed the basic moiety of Lys as detrimental for inhibition of MMP2 as compared to MMP9. Copyright © 2020 Elsevier Ltd. All rights reserved.

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