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 αvβ3 and MMP2 as a multitarget approach to deliver a synergistic blockade of tumor cell migration, invasion and metastasis. Accordingly, 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 to key pharmacophoric elements of MMP2 and αvβ3 RGD integrin.
Highlights
Molecules 2022, 27, 1249. https://Among cancer hallmarks [1], the deadliest component is invasion and metastasis, which refers to the ability of cancer cells to propagate from the original site to other tissues and produce secondary lesions
Starting from a work reported by Kessler and collaborators [23], who developed ligands based on the the knowledge of the binding mode vβ3 integrin we reasoned suchas pharmacotyrosine scaffold and towards studied theαeffect of the hydroxamic acid group compared to the carboxylic acid group for the interaction with
The tyrosine-based RGD pepknowledge of the binding mode αv β3or integrin we reasoned pharmacophore tidomimetic developed by Kessler consists of atowards carboxylic hydroxamic acidsuch moiety checould be found in the matrix metalloproteinase-2 (MMP2) catalytic site, too
Summary
Among cancer hallmarks [1], the deadliest component is invasion and metastasis, which refers to the ability of cancer cells to propagate from the original site to other tissues and produce secondary lesions. Tumor angiogenesis is a key step of this process and refers to the development of cancer blood vessel deriving from existing vasculature. Formed blood cancer vessels allow both primary cancer lesion to grow and cancer cells to invade adjacent tissues, disseminate in the blood stream and spread throughout the body. 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 pro-angiogenic 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) [2]. VEGF- and VEGFR-targeted monotherapies have shown only a reduced overall survival and progression-free survival [3]
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