Identification of highly potent and selective MMP2 inhibitors addressing the S1' subsite with d-proline-based compounds

Elena Lenci; Riccardo Innocenti; Tommaso Di Francescantonio; Gloria Menchi; Francesca Bianchini; Alessandro Contini; Andrea Trabocchi

doi:10.1016/j.bmc.2019.03.043

Identification of highly potent and selective MMP2 inhibitors addressing the S1' subsite with d-proline-based compounds

Bioorg Med Chem. 2019 May 1;27(9):1891-1902. doi: 10.1016/j.bmc.2019.03.043. Epub 2019 Mar 22.

Authors

Elena Lenci¹, Riccardo Innocenti¹, Tommaso Di Francescantonio¹, Gloria Menchi², Francesca Bianchini³, Alessandro Contini⁴, Andrea Trabocchi⁵

Affiliations

¹ Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.
² 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.
³ Interdepartmental Center for Preclinical Development of Molecular Imaging (CISPIM), University of Florence, Viale Morgagni 85, 50134 Florence, Italy; Department of Clinical and Experimental Biomedical Science "Mario Serio", University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
⁴ Department of Pharmaceutical Sciences, University of Milan, Via Venezian 21, I-20133 Milan, Italy.
⁵ 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: andrea.trabocchi@unifi.it.

PMID: 30926311
DOI: 10.1016/j.bmc.2019.03.043

Abstract

MMP2 and MMP9, also called gelatinases, play a primary role in the angiogenic switch, as a fundamental step of tumor progression, and show high degree of structural similarity. Clinically successful gelatinase inhibitors need to be highly selective as opposite effects have been found for the two enzymes, and the S1' subsite is the major driver to attain selective and potent inhibitors. The synthesis of d-proline-derived hydroxamic acids containing diverse appendages at the amino group, varying in length and decoration allowed to give insight on the MMP2/MMP9 selectivity around the S1' subsite, resulting in the identification of sub-nanomolar compounds with high selectivity up to 730. Molecular docking studies revealed the existence of an additional hydrophobic channel at the bottom of S1' subsite for MMP2 enzyme useful to drive selectivity towards such gelatinase.

Keywords: Amino acids; Angiogenesis; Drug discovery; Enzyme inhibition; Matrix metalloproteinase; Peptidomimetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Binding Sites
Cell Line, Tumor
Cell Survival / drug effects
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / metabolism
Matrix Metalloproteinase 2 / chemistry*
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / chemistry
Matrix Metalloproteinase 9 / metabolism
Matrix Metalloproteinase Inhibitors / chemistry*
Matrix Metalloproteinase Inhibitors / metabolism
Matrix Metalloproteinase Inhibitors / pharmacology
Molecular Docking Simulation
Proline / chemistry*
Protein Structure, Tertiary
Sequence Alignment
Structure-Activity Relationship

Substances

Hydroxamic Acids
Matrix Metalloproteinase Inhibitors
Proline
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9