Identification of a Common Pharmacophore for Binding to MMP2 and RGD Integrin: Towards a Multitarget Approach to Inhibit Cancer Angiogenesis and Metastasis

Abstract

During tumor angiogenesis different growth factors, cytokines and other molecules interact closely with each other to facilitate tumor cell invasion and metastatic diffusion. 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). Considering the poor efficacy of cancer angiogenesis monotherapies, we reasoned combining the inhibition of αv β3 and MMP2 as a multitarget approach to deliver a synergistic blockade of tumor cell migra-tion, invasion and metastasis. Accordingly, we identified a common pharmacophore in the binding cavity of MMP2 and αv β3, demonstrating such approach with the design, synthesis and bioas-says of tyrosine-derived peptidomimetics carrying the necessary functional groups to bind to key pharmacophoric elements of MMP2 and αv β3 RGD integrin.