Development of peptidomimetic gelatinase inhibitors for targeting tumor angiogenesis

Matrix Metallo-Proteases (MMPs) subfamily of gelatinases (MMP-2 and MMP-9) are zinc-containing extracellular proteases which are overexpressed in numerous aggressive malignant tumours. Due to their proteolytic activity, they play a role in cellular signalling pathways, and they also interact with membrane receptors such as αVβ3 and α5β1 integrins, determining fundamental processes in tumour metastasis as angiogenesis and cellular migration. The development of L-Tyrosine-derived inhibitors of αVβ3/α5β1 integrins is reported. We reasoned such RGD integrin ligands display a similar pharmacophore to those of MMPs inhibitors. Thus, we synthesized molecules analogous to those reported, to verify if it were possible to obtain integrin/gelatinase multitarget inhibitors. The synthesized molecules were variously functionalized with appropriate FGs (an α-arylsulfonamide group, a terminal basic group, and a chelating group) able to interact with the corresponding amino acid residues in the enzyme active site. The synthesized molecules were assayed toward MMP-2 and MMP-9. Some tested molecules demonstrated to possess good selective inhibitory activity within the gelatinase subfamily. Finally, molecular docking calculations were performed to identify the ligand-protein interactions and to rationalize the binding affinity of the most active compound.