Discovery of Z1362873773: a novel fascin inhibitor from a large chemical library for colorectal cancer
Abstract Metastasis is one of the leading causes of cancer-related death worldwide. Fascin, a protein that bundles actin filaments to produce protrusions in cancer cells, plays a significant role in the enhancement of cell migration. This protein has been shown that the overexpression of this protei...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-96457-x |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850204039977893888 |
|---|---|
| author | Alejandro Rodríguez-Martínez Lucía Giraldo-Ruiz María C. Ramos Irene Luque Diogo Ribeiro Fátima Postigo-Corrales Begoña Alburquerque-González Silvia Montoro-García Ana Belén Arroyo-Rodríguez Pablo Conesa-Zamora Ana María Hurtado Ginés Luengo-Gil Horacio Pérez-Sánchez |
| author_facet | Alejandro Rodríguez-Martínez Lucía Giraldo-Ruiz María C. Ramos Irene Luque Diogo Ribeiro Fátima Postigo-Corrales Begoña Alburquerque-González Silvia Montoro-García Ana Belén Arroyo-Rodríguez Pablo Conesa-Zamora Ana María Hurtado Ginés Luengo-Gil Horacio Pérez-Sánchez |
| author_sort | Alejandro Rodríguez-Martínez |
| collection | DOAJ |
| description | Abstract Metastasis is one of the leading causes of cancer-related death worldwide. Fascin, a protein that bundles actin filaments to produce protrusions in cancer cells, plays a significant role in the enhancement of cell migration. This protein has been shown that the overexpression of this protein is related to the appearance of different types of cancer, such as colorectal cancer. In this study, we conducted in silico screening of the Enamine library, a compound library with a broad chemical space. Using a ligand-based virtual screening approach based on the pharmacophore model of G2, we identified the predicted inhibitors. First, these compounds were validated by physicochemical analysis. Differential scanning calorimetry (DSF) was used to study the binding between the predicted compounds and fascin protein, followed by an F-actin bundling assay to determine which compounds inhibited the bundling function of fascin. Z1362873773, which exhibited binding to fascin and inhibited F-actin bundling, was further tested in cell cultures to assess its effects on cancer cell viability and migration as well as in organoid models to evaluate potential cytotoxicity. Finally, we established a protocol that can be applied to discover anti-fascin agents from diverse compound libraries. A new molecule has been identified with considerable fascin inhibitory and migration-arresting capacity, which may lead to the development of new therapies to treat cancer. |
| format | Article |
| id | doaj-art-fcd76cd0e8e943c08294ce98348de656 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-fcd76cd0e8e943c08294ce98348de6562025-08-20T02:11:22ZengNature PortfolioScientific Reports2045-23222025-04-0115111510.1038/s41598-025-96457-xDiscovery of Z1362873773: a novel fascin inhibitor from a large chemical library for colorectal cancerAlejandro Rodríguez-Martínez0Lucía Giraldo-Ruiz1María C. Ramos2Irene Luque3Diogo Ribeiro4Fátima Postigo-Corrales5Begoña Alburquerque-González6Silvia Montoro-García7Ana Belén Arroyo-Rodríguez8Pablo Conesa-Zamora9Ana María Hurtado10Ginés Luengo-Gil11Horacio Pérez-Sánchez12Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC), UCAM Universidad Católica de Murcia (UCAM)Departamento de Química Física, Instituto de Biotecnología y Unidad de Excelencia de Química aplicada a Biomedicina y Medioambiente, Universidad de GranadaFundación MEDINA, PTS Health Sciences Technology ParkDepartamento de Química Física, Instituto de Biotecnología y Unidad de Excelencia de Química aplicada a Biomedicina y Medioambiente, Universidad de GranadaGenetics, Molecular Pathology and Rare Diseases Research Group, Universidad Católica de Murcia (UCAM)Genetics, Molecular Pathology and Rare Diseases Research Group, Universidad Católica de Murcia (UCAM)Genetics, Molecular Pathology and Rare Diseases Research Group, Universidad Católica de Murcia (UCAM)Genetics, Molecular Pathology and Rare Diseases Research Group, Universidad Católica de Murcia (UCAM)Molecular Pathology and Pharmacogenetics Research Group, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital General Universitario Santa LucíaGenetics, Molecular Pathology and Rare Diseases Research Group, Universidad Católica de Murcia (UCAM)Genetics, Molecular Pathology and Rare Diseases Research Group, Universidad Católica de Murcia (UCAM)Genetics, Molecular Pathology and Rare Diseases Research Group, Universidad Católica de Murcia (UCAM)Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC), UCAM Universidad Católica de Murcia (UCAM)Abstract Metastasis is one of the leading causes of cancer-related death worldwide. Fascin, a protein that bundles actin filaments to produce protrusions in cancer cells, plays a significant role in the enhancement of cell migration. This protein has been shown that the overexpression of this protein is related to the appearance of different types of cancer, such as colorectal cancer. In this study, we conducted in silico screening of the Enamine library, a compound library with a broad chemical space. Using a ligand-based virtual screening approach based on the pharmacophore model of G2, we identified the predicted inhibitors. First, these compounds were validated by physicochemical analysis. Differential scanning calorimetry (DSF) was used to study the binding between the predicted compounds and fascin protein, followed by an F-actin bundling assay to determine which compounds inhibited the bundling function of fascin. Z1362873773, which exhibited binding to fascin and inhibited F-actin bundling, was further tested in cell cultures to assess its effects on cancer cell viability and migration as well as in organoid models to evaluate potential cytotoxicity. Finally, we established a protocol that can be applied to discover anti-fascin agents from diverse compound libraries. A new molecule has been identified with considerable fascin inhibitory and migration-arresting capacity, which may lead to the development of new therapies to treat cancer.https://doi.org/10.1038/s41598-025-96457-x |
| spellingShingle | Alejandro Rodríguez-Martínez Lucía Giraldo-Ruiz María C. Ramos Irene Luque Diogo Ribeiro Fátima Postigo-Corrales Begoña Alburquerque-González Silvia Montoro-García Ana Belén Arroyo-Rodríguez Pablo Conesa-Zamora Ana María Hurtado Ginés Luengo-Gil Horacio Pérez-Sánchez Discovery of Z1362873773: a novel fascin inhibitor from a large chemical library for colorectal cancer Scientific Reports |
| title | Discovery of Z1362873773: a novel fascin inhibitor from a large chemical library for colorectal cancer |
| title_full | Discovery of Z1362873773: a novel fascin inhibitor from a large chemical library for colorectal cancer |
| title_fullStr | Discovery of Z1362873773: a novel fascin inhibitor from a large chemical library for colorectal cancer |
| title_full_unstemmed | Discovery of Z1362873773: a novel fascin inhibitor from a large chemical library for colorectal cancer |
| title_short | Discovery of Z1362873773: a novel fascin inhibitor from a large chemical library for colorectal cancer |
| title_sort | discovery of z1362873773 a novel fascin inhibitor from a large chemical library for colorectal cancer |
| url | https://doi.org/10.1038/s41598-025-96457-x |
| work_keys_str_mv | AT alejandrorodriguezmartinez discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT luciagiraldoruiz discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT mariacramos discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT ireneluque discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT diogoribeiro discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT fatimapostigocorrales discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT begonaalburquerquegonzalez discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT silviamontorogarcia discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT anabelenarroyorodriguez discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT pabloconesazamora discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT anamariahurtado discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT ginesluengogil discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer AT horacioperezsanchez discoveryofz1362873773anovelfascininhibitorfromalargechemicallibraryforcolorectalcancer |