Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells.

Proceedings of the National Academy of Sciences of the United States of America 2020 Nov 24

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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 proline-derived modules (ProMs) to succeed in developing a nanomolar inhibitor ([Formula: see text] 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 suppression of cancer metastasis by inhibiting a crucial protein-protein interaction involved in actin filament processing and cell migration. Copyright © 2020 the Author(s). Published by PNAS.

Citation

Matthias Barone, Matthias Müller, Slim Chiha, Jiang Ren, Dominik Albat, Arne Soicke, Stephan Dohmen, Marco Klein, Judith Bruns, Maarten van Dinther, Robert Opitz, Peter Lindemann, Monika Beerbaum, Kathrin Motzny, Yvette Roske, Peter Schmieder, Rudolf Volkmer, Marc Nazaré, Udo Heinemann, Hartmut Oschkinat, Peter Ten Dijke, Hans-Günther Schmalz, Ronald Kühne. Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America. 2020 Nov 24;117(47):29684-29690