Tyrosine-derived Peptidomimetics as Dual Gelatinase Inhibitors and Integrin Ligands

During tumor angiogenesis different growth factors, cytokines and other molecules interact closely with each other to facilitate tumor cell invasion and metastatic diffusion. Among many different proangiogenic factors, the most intensively studied as molecular targets in anti-angiogenic therapies are vascular endothelial growth factor (VEGF) and related receptors, integrin receptors and matrix metalloproteinases (MMPs).1 During the last years we developed new D-proline-derived hydroxamic acids as selective inhibitors of MMP2 and MMP92 and we identified a compound with an interesting inhibition profile towards MMP9 and CAII.3 Starting from such results, we got interested in the study of the combined effect of both RGD integrin ligands and gelatinase inhibitors towards cell migration and invasion in vitro. Thus, we identified a common pharmacophore in the binding cavity of MMP2 and αVβ3, demonstrating such approach with the design, synthesis and bioassays of tyrosine-derived peptidomimetics carrying the necessary functional groups to bind either these two molecular targets involved in tumor angiogenesis. The synthetic strategy allowed to furnish a pool of peptidomimetics varying in the three key functional groups, and subsequent bioassays towards purified proteins and on a melanoma cell line allowed to identify a hydroxamic acid derivative capable of displaying dual activity towards MMP2 and αvβ3 RGD integrin (Figure 1).4 Cell based assays corroborated the bioactivity profile of the compound, and molecular docking calculations allowed to ascertain the binding mode within the two protein cavities, confirming the hypothesized common binding region for the two proteins.