ArticleProceedings of the National Academy of Sciences of the United States of America2020
Designed nanomolar small-molecule inhibitors of Ena/VASP EVH1 interaction impair invasion and extravasation of breast cancer cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 36 citations in OpenAlex.
- Targeting collagen biosynthesis by small molecules inhibiting the function of the peptide-substrate-binding domain of collagen prolyl 4-hydroxylases.Scientific reports · 2026Article
- Pan-cancer analysis of HOMER1 in hepatocellular carcinoma revealing diagnostic potential and immune landscape with experimental validation.Discover oncology · 2025Article
- A Polyproline Type II Peptidomimetic Disrupts a Grb2 SH3C Domain Protein-Protein Interaction Implicated in Breast Cancer.Chembiochem : a European journal of chemical biology · 2025Article
- Ena/VASP-EVH1 inhibition prevents chemotaxis and metastasis by blocking the EVH1-WAVE2 interaction.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Sequestration of ribosomal subunits as inactive 80S by targeting eIF6 limits mitotic exit and cancer progression.Nucleic acids research · 2025Article
- Structure-based drug design with equivariant diffusion models.Nature computational science · 2024Article
- Upregulation of ENAH by a PI3K/AKT/β-catenin cascade promotes oral cancer cell migration and growth via an ITGB5/Src axis.Cellular & molecular biology letters · 2024Article
- Insights into the Interaction Landscape of the EVH1 Domain of Mena.Biochemistry · 2024Article
- Probing the protrusions: lamellipodia and filopodia in cancer invasion and beyond.Mechanobiology in medicine · 2024Review
- Kinetic trapping organizes actin filaments within liquid-like protein droplets.Nature communications · 2024Article
- The Role of Vasodilator-stimulated Phosphoproteins in the Development of Malignant Tumors.Current cancer drug targets · 2024Review
- Comparison of tumor growth assessment using GFP fluorescence and DiI labeling in a zebrafish xenograft model.Cancer biology & therapy · 2023Article
- Oncogenic BRAF noncanonically promotes tumor metastasis by mediating VASP phosphorylation and filopodia formation.Oncogene · 2023Article
- Review
- A Hybrid Machine Learning Approach to Screen Optimal Predictors for the Classification of Primary Breast Tumors from Gene Expression Microarray Data.Diagnostics (Basel, Switzerland) · 2023Article
- ArpC5 isoforms regulate Arp2/3 complex-dependent protrusion through differential Ena/VASP positioning.Science advances · 2023Article
- Synthetic α-Helical Peptides as Potential Inhibitors of the ACE2 SARS-CoV-2 Interaction.Chembiochem : a European journal of chemical biology · 2022Article
- Native proline-rich motifs exploit sequence context to target actin-remodeling Ena/VASP protein ENAH.eLife · 2022Article
- Ena/VASP Protein-Mediated Actin Polymerization Contributes to Naïve CD8Frontiers in immunology · 2022Article
- Migration and homeostasis of regulatory T cells in rheumatoid arthritis.Frontiers in immunology · 2022Review
Corrections and comments
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Authors and funding
23 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.