Barone, Matthias ORCID: 0000-0002-6554-6464, Mueller, Matthias, Chiha, Slim, Ren, Jiang, Albat, Dominik, Soicke, Arne, Dohmen, Stephan, Klein, Marco, Bruns, Judith, van Dinther, Maarten, Opitz, Robert, Lindemann, Peter, Beerbaum, Monika, Motzny, Kathrin, Roske, Yvette, Schmieder, Peter, Volkmer, Rudolf, Nazare, Marc, Heinemann, Udo ORCID: 0000-0002-8191-3850, Oschkinat, Hartmut, ten Dijke, Peter, Schmalz, Hans-Guenther ORCID: 0000-0003-0489-1827 and Kuehne, Ronald (2020). Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells. Proc. Natl. Acad. Sci. U. S. A., 117 (47). S. 29684 - 29691. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Barone, MatthiasUNSPECIFIEDorcid.org/0000-0002-6554-6464UNSPECIFIED
Mueller, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chiha, SlimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ren, JiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Albat, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soicke, ArneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dohmen, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruns, JudithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Dinther, MaartenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Opitz, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindemann, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beerbaum, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motzny, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roske, YvetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmieder, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volkmer, RudolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nazare, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinemann, UdoUNSPECIFIEDorcid.org/0000-0002-8191-3850UNSPECIFIED
Oschkinat, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
ten Dijke, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmalz, Hans-GuentherUNSPECIFIEDorcid.org/0000-0003-0489-1827UNSPECIFIED
Kuehne, RonaldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-310798
DOI: 10.1073/pnas.2007213117
Journal or Publication Title: Proc. Natl. Acad. Sci. U. S. A.
Volume: 117
Number: 47
Page Range: S. 29684 - 29691
Date: 2020
Publisher: NATL ACAD SCIENCES
Place of Publication: WASHINGTON
ISSN: 0027-8424
Language: English
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Organic Chemistry
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
STEREOSELECTIVE-SYNTHESIS; ACTIN DYNAMICS; LIGAND; COMPLEX; BINDING; INVADOPODIA; VASP; WAVE; LAMELLIPODIN; EXPRESSIONMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/31079

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