Zebrafish phenotypic screen identifies novel Notch antagonists
Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer
2017
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| Online Access: | http://psasir.upm.edu.my/id/eprint/63740/ http://psasir.upm.edu.my/id/eprint/63740/1/Zebrafish%20phenotypic%20screen%20identifies%20novel%20Notch%20antagonists.pdf |
| _version_ | 1848854858284662784 |
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| author | Velaithan, Vithya Okuda, Kazuhide Shaun Mei, Fong Ng Samat, Norazwana Sze, Wei Leong Faudzi, Siti Munirah Mohd Abas, Faridah Shaari, Khozirah Sok, Ching Cheong Pei, Jean Tan Patel, Vyomesh |
| author_facet | Velaithan, Vithya Okuda, Kazuhide Shaun Mei, Fong Ng Samat, Norazwana Sze, Wei Leong Faudzi, Siti Munirah Mohd Abas, Faridah Shaari, Khozirah Sok, Ching Cheong Pei, Jean Tan Patel, Vyomesh |
| author_sort | Velaithan, Vithya |
| building | UPM Institutional Repository |
| collection | Online Access |
| description | Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent. |
| first_indexed | 2025-11-15T11:16:33Z |
| format | Article |
| id | upm-63740 |
| institution | Universiti Putra Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-15T11:16:33Z |
| publishDate | 2017 |
| publisher | Springer |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | upm-637402018-11-30T04:18:37Z http://psasir.upm.edu.my/id/eprint/63740/ Zebrafish phenotypic screen identifies novel Notch antagonists Velaithan, Vithya Okuda, Kazuhide Shaun Mei, Fong Ng Samat, Norazwana Sze, Wei Leong Faudzi, Siti Munirah Mohd Abas, Faridah Shaari, Khozirah Sok, Ching Cheong Pei, Jean Tan Patel, Vyomesh Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent. Springer 2017-04 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/63740/1/Zebrafish%20phenotypic%20screen%20identifies%20novel%20Notch%20antagonists.pdf Velaithan, Vithya and Okuda, Kazuhide Shaun and Mei, Fong Ng and Samat, Norazwana and Sze, Wei Leong and Faudzi, Siti Munirah Mohd and Abas, Faridah and Shaari, Khozirah and Sok, Ching Cheong and Pei, Jean Tan and Patel, Vyomesh (2017) Zebrafish phenotypic screen identifies novel Notch antagonists. Investigational New Drugs, 35 (2). pp. 166-179. ISSN 0167-6997; ESSN: 1573-0646 10.1007/s10637-016-0423-y |
| spellingShingle | Velaithan, Vithya Okuda, Kazuhide Shaun Mei, Fong Ng Samat, Norazwana Sze, Wei Leong Faudzi, Siti Munirah Mohd Abas, Faridah Shaari, Khozirah Sok, Ching Cheong Pei, Jean Tan Patel, Vyomesh Zebrafish phenotypic screen identifies novel Notch antagonists |
| title | Zebrafish phenotypic screen identifies novel Notch antagonists |
| title_full | Zebrafish phenotypic screen identifies novel Notch antagonists |
| title_fullStr | Zebrafish phenotypic screen identifies novel Notch antagonists |
| title_full_unstemmed | Zebrafish phenotypic screen identifies novel Notch antagonists |
| title_short | Zebrafish phenotypic screen identifies novel Notch antagonists |
| title_sort | zebrafish phenotypic screen identifies novel notch antagonists |
| url | http://psasir.upm.edu.my/id/eprint/63740/ http://psasir.upm.edu.my/id/eprint/63740/ http://psasir.upm.edu.my/id/eprint/63740/1/Zebrafish%20phenotypic%20screen%20identifies%20novel%20Notch%20antagonists.pdf |