Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells
Open Access
- 24 November 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (47), 29684-29690
- https://doi.org/10.1073/pnas.2007213117
Abstract
Battling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular interactions with their EVH1 domains, are promising targets for pharmaceutical intervention. However, protein-protein interactions involving proline-rich segments are notoriously difficult to address by small molecules. Hence, structure-based design efforts in combination with the chemical synthesis of additional molecular entities are required. Building on a previously developed nonpeptidic micromolar inhibitor, we determined 22 crystal structures of ENAH EVH1 in complex with inhibitors and rationally extended our library of conformationally defined prolinederived modules (ProMs) to succeed in developing a nanomolar inhibitor (K-d = 120 nM, MW = 734 Da). In contrast to the previous inhibitor, the optimized compounds reduced extravasation of invasive breast cancer cells in a zebrafish model. This study represents an example of successful, structure-guided development of low molecular weight inhibitors specifically and selectively addressing a proline-rich sequence-recognizing domain that is characterized by a shallow epitope lacking defined binding pockets. The evolved high-affinity inhibitor may now serve as a tool in validating the basic therapeutic concept, i.e., the sup pression of cancer metastasis by inhibiting a crucial protein- protein interaction involved in actin filament processing and cell migration.This publication has 59 references indexed in Scilit:
- Therapy for metastatic melanoma: the past, present, and futureBMC Medicine, 2012
- Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung CancersScience Translational Medicine, 2012
- Phosphorylation of vasodilator‐stimulated phosphoprotein Ser239 suppresses filopodia and invadopodia in colon cancerInternational Journal of Cancer, 2011
- Ena drives invasive macrophage migration in Drosophila embryosDisease Models & Mechanisms, 2011
- The Cooperation between hMena Overexpression and HER2 Signalling in Breast CancerPLOS ONE, 2010
- Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumorsBreast Cancer Research, 2010
- Actin machinery and mechanosensitivity in invadopodia, podosomes and focal adhesionsJournal of Cell Science, 2009
- Integrins in cell migration – the actin connectionJournal of Cell Science, 2009
- A Mena Invasion Isoform Potentiates EGF-Induced Carcinoma Cell Invasion and MetastasisDevelopmental Cell, 2008
- Molecular mechanisms of invadopodium formationThe Journal of cell biology, 2005