Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation
Abstract Deubiquitinating enzymes (DUBs) are key regulators of cellular homoeostasis, and their dysregulation is associated with several human diseases. The ovarian tumour protease (OTU) family of DUBs are biochemically well-characterised and of therapeutic interest, yet only a few tool compounds ex...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01410-8 |
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| author | Aini Vuorinen Cassandra R. Kennedy Katherine A. McPhie William McCarthy Jonathan Pettinger J. Mark Skehel David House Jacob T. Bush Katrin Rittinger |
| author_facet | Aini Vuorinen Cassandra R. Kennedy Katherine A. McPhie William McCarthy Jonathan Pettinger J. Mark Skehel David House Jacob T. Bush Katrin Rittinger |
| author_sort | Aini Vuorinen |
| collection | DOAJ |
| description | Abstract Deubiquitinating enzymes (DUBs) are key regulators of cellular homoeostasis, and their dysregulation is associated with several human diseases. The ovarian tumour protease (OTU) family of DUBs are biochemically well-characterised and of therapeutic interest, yet only a few tool compounds exist to study their cellular function and therapeutic potential. Here we present a chemoproteomics fragment screening platform for identifying novel DUB-specific hit matter, that combines activity-based protein profiling with high-throughput chemistry direct-to-biology optimisation to enable rapid elaboration of initial fragment hits against OTU DUBs. Applying these approaches, we identify an enantioselective covalent fragment for OTUD7B, and validate it using chemoproteomics and biochemical DUB activity assays. |
| format | Article |
| id | doaj-art-139954714e30474fb73ffa5a4e8f6ab1 |
| institution | Kabale University |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-139954714e30474fb73ffa5a4e8f6ab12025-01-19T12:13:09ZengNature PortfolioCommunications Chemistry2399-36692025-01-018111210.1038/s42004-025-01410-8Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisationAini Vuorinen0Cassandra R. Kennedy1Katherine A. McPhie2William McCarthy3Jonathan Pettinger4J. Mark Skehel5David House6Jacob T. Bush7Katrin Rittinger8Proteomics Science Technology Platform, The Francis Crick InstituteMolecular Structure of Cell Signalling Laboratory, The Francis Crick InstituteMolecular Structure of Cell Signalling Laboratory, The Francis Crick InstituteMolecular Structure of Cell Signalling Laboratory, The Francis Crick InstituteCrick-GSK Biomedical LinkLabs, GSK, StevenageProteomics Science Technology Platform, The Francis Crick InstituteCrick-GSK Biomedical LinkLabs, GSK, StevenageCrick-GSK Biomedical LinkLabs, GSK, StevenageMolecular Structure of Cell Signalling Laboratory, The Francis Crick InstituteAbstract Deubiquitinating enzymes (DUBs) are key regulators of cellular homoeostasis, and their dysregulation is associated with several human diseases. The ovarian tumour protease (OTU) family of DUBs are biochemically well-characterised and of therapeutic interest, yet only a few tool compounds exist to study their cellular function and therapeutic potential. Here we present a chemoproteomics fragment screening platform for identifying novel DUB-specific hit matter, that combines activity-based protein profiling with high-throughput chemistry direct-to-biology optimisation to enable rapid elaboration of initial fragment hits against OTU DUBs. Applying these approaches, we identify an enantioselective covalent fragment for OTUD7B, and validate it using chemoproteomics and biochemical DUB activity assays.https://doi.org/10.1038/s42004-025-01410-8 |
| spellingShingle | Aini Vuorinen Cassandra R. Kennedy Katherine A. McPhie William McCarthy Jonathan Pettinger J. Mark Skehel David House Jacob T. Bush Katrin Rittinger Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation Communications Chemistry |
| title | Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation |
| title_full | Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation |
| title_fullStr | Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation |
| title_full_unstemmed | Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation |
| title_short | Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation |
| title_sort | enantioselective otud7b fragment discovery through chemoproteomics screening and high throughput optimisation |
| url | https://doi.org/10.1038/s42004-025-01410-8 |
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