Broad-spectrum ubiquitin-specific protease inhibition as a mechanism for the cytotoxicity of YM155 in cancers
Abstract Protein ubiquitination is a dynamic and reversible process involved in gene transcription, protein metabolism, and cellular apoptosis. Ubiquitin specific proteases (USPs), as the largest family of deubiquitinating enzymes, are able to remove the ubiquitin from target proteins, rescuing them...
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| Format: | Article |
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Nature Portfolio
2025-04-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-88761-3 |
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| author | Xiang Li Na He Yan Lv Haiyue Wang Ming Zhang Heiyan Zhai Zhen Yang Yi Yang Dagang Guo Zhixiang Cao Yiyou Chen |
| author_facet | Xiang Li Na He Yan Lv Haiyue Wang Ming Zhang Heiyan Zhai Zhen Yang Yi Yang Dagang Guo Zhixiang Cao Yiyou Chen |
| author_sort | Xiang Li |
| collection | DOAJ |
| description | Abstract Protein ubiquitination is a dynamic and reversible process involved in gene transcription, protein metabolism, and cellular apoptosis. Ubiquitin specific proteases (USPs), as the largest family of deubiquitinating enzymes, are able to remove the ubiquitin from target proteins, rescuing them from degradation. Here, we characterized the small molecule antitumor agent YM155 as a broad-spectrum USP inhibitor. By inhibiting the deubiquitinase activity of multiple USPs, YM155 causes the degradation of oncogenic substrate proteins, such as c-Myc and intracellular domain of Notch1. In cancers driven by these proteins, YM155 induces profound cell apoptosis and markedly inhibits tumor growth in xenograft models. Together, these findings demonstrate that YM155 is a broad-spectrum USP inhibitor, and a potential drug candidate for cancers which depend on hyper-active oncogenic proteins that are regulated by the ubiquitin-proteasome pathway. |
| format | Article |
| id | doaj-art-a864ce0fe85d43fc8778ee6f1cdac7ca |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-a864ce0fe85d43fc8778ee6f1cdac7ca2025-08-20T02:25:35ZengNature PortfolioScientific Reports2045-23222025-04-011511810.1038/s41598-025-88761-3Broad-spectrum ubiquitin-specific protease inhibition as a mechanism for the cytotoxicity of YM155 in cancersXiang Li0Na He1Yan Lv2Haiyue Wang3Ming Zhang4Heiyan Zhai5Zhen Yang6Yi Yang7Dagang Guo8Zhixiang Cao9Yiyou Chen10China R&D Center, Cothera Bioscience, Inc.China R&D Center, Cothera Bioscience, Inc.China R&D Center, Cothera Bioscience, Inc.China R&D Center, Cothera Bioscience, Inc.China R&D Center, Cothera Bioscience, Inc.China R&D Center, Cothera Bioscience, Inc.China R&D Center, Cothera Bioscience, Inc.China R&D Center, Cothera Bioscience, Inc.China R&D Center, Cothera Bioscience, Inc.China R&D Center, Cothera Bioscience, Inc.Cothera Bioscience, Inc.Abstract Protein ubiquitination is a dynamic and reversible process involved in gene transcription, protein metabolism, and cellular apoptosis. Ubiquitin specific proteases (USPs), as the largest family of deubiquitinating enzymes, are able to remove the ubiquitin from target proteins, rescuing them from degradation. Here, we characterized the small molecule antitumor agent YM155 as a broad-spectrum USP inhibitor. By inhibiting the deubiquitinase activity of multiple USPs, YM155 causes the degradation of oncogenic substrate proteins, such as c-Myc and intracellular domain of Notch1. In cancers driven by these proteins, YM155 induces profound cell apoptosis and markedly inhibits tumor growth in xenograft models. Together, these findings demonstrate that YM155 is a broad-spectrum USP inhibitor, and a potential drug candidate for cancers which depend on hyper-active oncogenic proteins that are regulated by the ubiquitin-proteasome pathway.https://doi.org/10.1038/s41598-025-88761-3YM155A broad-spectrum USP inhibitorc-MycNotch1Ubiquitin-proteasome pathway |
| spellingShingle | Xiang Li Na He Yan Lv Haiyue Wang Ming Zhang Heiyan Zhai Zhen Yang Yi Yang Dagang Guo Zhixiang Cao Yiyou Chen Broad-spectrum ubiquitin-specific protease inhibition as a mechanism for the cytotoxicity of YM155 in cancers Scientific Reports YM155 A broad-spectrum USP inhibitor c-Myc Notch1 Ubiquitin-proteasome pathway |
| title | Broad-spectrum ubiquitin-specific protease inhibition as a mechanism for the cytotoxicity of YM155 in cancers |
| title_full | Broad-spectrum ubiquitin-specific protease inhibition as a mechanism for the cytotoxicity of YM155 in cancers |
| title_fullStr | Broad-spectrum ubiquitin-specific protease inhibition as a mechanism for the cytotoxicity of YM155 in cancers |
| title_full_unstemmed | Broad-spectrum ubiquitin-specific protease inhibition as a mechanism for the cytotoxicity of YM155 in cancers |
| title_short | Broad-spectrum ubiquitin-specific protease inhibition as a mechanism for the cytotoxicity of YM155 in cancers |
| title_sort | broad spectrum ubiquitin specific protease inhibition as a mechanism for the cytotoxicity of ym155 in cancers |
| topic | YM155 A broad-spectrum USP inhibitor c-Myc Notch1 Ubiquitin-proteasome pathway |
| url | https://doi.org/10.1038/s41598-025-88761-3 |
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