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): 29684-29690, 2020 11 24.
Article
em En
| MEDLINE
| ID: mdl-33184177
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 ([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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Neoplasias da Mama
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Moléculas de Adesão Celular
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Proteínas de Ligação a DNA
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Bibliotecas de Moléculas Pequenas
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Domínios e Motivos de Interação entre Proteínas
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Proteínas dos Microfilamentos
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Alemanha