Proteome selectivity profiling of photoaffinity probes derived from imidazopyrazine-kinase inhibitors
Abstract Kinases are attractive drug targets, but the design of highly selective kinase inhibitors remains challenging. Selectivity may be evaluated against a panel of kinases, or – preferred – in a complex proteome. Probes that allow photoaffinity-labeling of their targets can facilitate this proce...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01436-y |
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| _version_ | 1825197562376749056 |
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| author | Dimitris Korovesis Christel Mérillat Rita Derua Steven H. L. Verhelst |
| author_facet | Dimitris Korovesis Christel Mérillat Rita Derua Steven H. L. Verhelst |
| author_sort | Dimitris Korovesis |
| collection | DOAJ |
| description | Abstract Kinases are attractive drug targets, but the design of highly selective kinase inhibitors remains challenging. Selectivity may be evaluated against a panel of kinases, or – preferred – in a complex proteome. Probes that allow photoaffinity-labeling of their targets can facilitate this process. Here, we report photoaffinity probes based on the imidazopyrazine scaffold, which is found in several kinase inhibitors and drugs or drug candidates. By chemical proteomics experiments, we find a range of off-targets, which vary between the different probes. In silico analysis suggests that differences between probes may be related to the size, spatial arrangement and rigidity of the imidazopyrazine and its substituent at the 1-position. |
| format | Article |
| id | doaj-art-0f501843961d445d95c31af479437091 |
| institution | Kabale University |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-0f501843961d445d95c31af4794370912025-02-09T12:16:25ZengNature PortfolioCommunications Chemistry2399-36692025-02-01811810.1038/s42004-025-01436-yProteome selectivity profiling of photoaffinity probes derived from imidazopyrazine-kinase inhibitorsDimitris Korovesis0Christel Mérillat1Rita Derua2Steven H. L. Verhelst3Department of Cellular and Molecular Medicine, Laboratory of Chemical Biology, KU Leuven – University of LeuvenDepartment of Cellular and Molecular Medicine, Laboratory of Chemical Biology, KU Leuven – University of LeuvenDepartment of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, KU Leuven – University of LeuvenDepartment of Cellular and Molecular Medicine, Laboratory of Chemical Biology, KU Leuven – University of LeuvenAbstract Kinases are attractive drug targets, but the design of highly selective kinase inhibitors remains challenging. Selectivity may be evaluated against a panel of kinases, or – preferred – in a complex proteome. Probes that allow photoaffinity-labeling of their targets can facilitate this process. Here, we report photoaffinity probes based on the imidazopyrazine scaffold, which is found in several kinase inhibitors and drugs or drug candidates. By chemical proteomics experiments, we find a range of off-targets, which vary between the different probes. In silico analysis suggests that differences between probes may be related to the size, spatial arrangement and rigidity of the imidazopyrazine and its substituent at the 1-position.https://doi.org/10.1038/s42004-025-01436-y |
| spellingShingle | Dimitris Korovesis Christel Mérillat Rita Derua Steven H. L. Verhelst Proteome selectivity profiling of photoaffinity probes derived from imidazopyrazine-kinase inhibitors Communications Chemistry |
| title | Proteome selectivity profiling of photoaffinity probes derived from imidazopyrazine-kinase inhibitors |
| title_full | Proteome selectivity profiling of photoaffinity probes derived from imidazopyrazine-kinase inhibitors |
| title_fullStr | Proteome selectivity profiling of photoaffinity probes derived from imidazopyrazine-kinase inhibitors |
| title_full_unstemmed | Proteome selectivity profiling of photoaffinity probes derived from imidazopyrazine-kinase inhibitors |
| title_short | Proteome selectivity profiling of photoaffinity probes derived from imidazopyrazine-kinase inhibitors |
| title_sort | proteome selectivity profiling of photoaffinity probes derived from imidazopyrazine kinase inhibitors |
| url | https://doi.org/10.1038/s42004-025-01436-y |
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