Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells.
Animals
Breast Neoplasms
/ drug therapy
Cell Adhesion Molecules
/ metabolism
Cell Line, Tumor
Cell Movement
/ drug effects
DNA-Binding Proteins
/ metabolism
Female
Humans
Jurkat Cells
Microfilament Proteins
/ metabolism
Phosphoproteins
/ metabolism
Proline
/ metabolism
Protein Binding
/ drug effects
Protein Interaction Domains and Motifs
/ drug effects
Small Molecule Libraries
/ pharmacology
Zebrafish
metastasis
peptide mimetics
proline-rich motif
protein–protein interactions
small molecules
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
24 11 2020
24 11 2020
Historique:
pubmed:
14
11
2020
medline:
12
1
2021
entrez:
13
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33184177
pii: 2007213117
doi: 10.1073/pnas.2007213117
pmc: PMC7703624
doi:
Substances chimiques
Cell Adhesion Molecules
0
DNA-Binding Proteins
0
ENA-VASP proteins
0
Microfilament Proteins
0
Phosphoproteins
0
Small Molecule Libraries
0
vasodilator-stimulated phosphoprotein
0
Proline
9DLQ4CIU6V
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
29684-29690Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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