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| Item Type: | Article |
|---|---|
| Title: | Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells |
| Creators: |
Barone, M.  ORCID: https://orcid.org/0000-0002-6554-6464, Müller, M., Chiha, S., Ren, J., Albat, D., Soicke, A., Dohmen, S., Klein, M., Bruns, J., van Dinther, M., Opitz, R. ORCID: https://orcid.org/0000-0003-3143-0997, Lindemann, P. ORCID: https://orcid.org/0000-0002-8224-3764, Beerbaum, M., Motzny, K., Roske, Y. ORCID: https://orcid.org/0000-0001-6237-388X, Schmieder, P. ORCID: https://orcid.org/0000-0001-9968-9327, Volkmer, R., Nazaré, M. ORCID: https://orcid.org/0000-0002-1602-2330, Heinemann, U. ORCID: https://orcid.org/0000-0002-8191-3850, Oschkinat, H., Ten Dijke, P., Schmalz, H.G. ORCID: https://orcid.org/0000-0003-0489-1827 and Kühne, R.
|
| 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 proline-derived 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 suppression of cancer metastasis by inhibiting a crucial protein-protein interaction involved in actin filament processing and cell migration. SIGNIFICANCE: Protein–protein interactions mediated by proline-rich motifs are involved in regulation of many important signaling cascades. These motifs belong to the most abundant recognition motifs in the eukaryotic genome and preferentially adopt a left-handed polyproline helix II, a secondary structure element that has been notoriously difficult to mimic with small molecules. Here, we present a structure-guided design effort yielding a toolkit of chemical entities that enables rational construction of selective small molecule inhibitors for these protein domains. We succeeded in developing an inhibitor for the Ena/VASP protein family that is active in vivo and reduces extravasation of invasive breast cancer cells in a zebrafish model. |
| Keywords: | Protein-Protein Interactions, Metastasis, Small Molecules, Peptide Mimetics, Proline-Rich Motif, Animals, Zebrafish |
| Source: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Volume: | 117 |
| Number: | 47 |
| Page Range: | 29684-29690 |
| Date: | 24 November 2020 |
| Official Publication: | https://doi.org/10.1073/pnas.2007213117 |
| PubMed: | View item in PubMed |
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