Systematic Exploration of Privileged Warheads for Covalent Kinase Drug Discovery
Kinase-targeted drug discovery for cancer therapy has advanced significantly in the last three decades. Currently, diverse kinase inhibitors or degraders have been reported, such as allosteric inhibitors, covalent inhibitors, macrocyclic inhibitors, and PROTAC degraders. Out of these, covalent kinas...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/15/11/1322 |
| _version_ | 1797466909879304192 |
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| author | Zheng Zhao Philip E. Bourne |
| author_facet | Zheng Zhao Philip E. Bourne |
| author_sort | Zheng Zhao |
| collection | DOAJ |
| description | Kinase-targeted drug discovery for cancer therapy has advanced significantly in the last three decades. Currently, diverse kinase inhibitors or degraders have been reported, such as allosteric inhibitors, covalent inhibitors, macrocyclic inhibitors, and PROTAC degraders. Out of these, covalent kinase inhibitors (CKIs) have been attracting attention due to their enhanced selectivity and exceptionally strong affinity. Eight covalent kinase drugs have been FDA-approved thus far. Here, we review current developments in CKIs. We explore the characteristics of the CKIs: the features of nucleophilic amino acids and the preferences of electrophilic warheads. We provide systematic insights into privileged warheads for repurposing to other kinase targets. Finally, we discuss trends in CKI development across the whole proteome. |
| first_indexed | 2024-03-09T18:45:14Z |
| format | Article |
| id | doaj.art-995478cade69420f89c732fb2d857dee |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T18:45:14Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-995478cade69420f89c732fb2d857dee2023-11-24T06:18:07ZengMDPI AGPharmaceuticals1424-82472022-10-011511132210.3390/ph15111322Systematic Exploration of Privileged Warheads for Covalent Kinase Drug DiscoveryZheng Zhao0Philip E. Bourne1School of Data Science and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22904, USASchool of Data Science and Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22904, USAKinase-targeted drug discovery for cancer therapy has advanced significantly in the last three decades. Currently, diverse kinase inhibitors or degraders have been reported, such as allosteric inhibitors, covalent inhibitors, macrocyclic inhibitors, and PROTAC degraders. Out of these, covalent kinase inhibitors (CKIs) have been attracting attention due to their enhanced selectivity and exceptionally strong affinity. Eight covalent kinase drugs have been FDA-approved thus far. Here, we review current developments in CKIs. We explore the characteristics of the CKIs: the features of nucleophilic amino acids and the preferences of electrophilic warheads. We provide systematic insights into privileged warheads for repurposing to other kinase targets. Finally, we discuss trends in CKI development across the whole proteome.https://www.mdpi.com/1424-8247/15/11/1322kinase inhibitorcovalent kinase inhibitorprivileged warheadnucleophilerational drug discovery |
| spellingShingle | Zheng Zhao Philip E. Bourne Systematic Exploration of Privileged Warheads for Covalent Kinase Drug Discovery Pharmaceuticals kinase inhibitor covalent kinase inhibitor privileged warhead nucleophile rational drug discovery |
| title | Systematic Exploration of Privileged Warheads for Covalent Kinase Drug Discovery |
| title_full | Systematic Exploration of Privileged Warheads for Covalent Kinase Drug Discovery |
| title_fullStr | Systematic Exploration of Privileged Warheads for Covalent Kinase Drug Discovery |
| title_full_unstemmed | Systematic Exploration of Privileged Warheads for Covalent Kinase Drug Discovery |
| title_short | Systematic Exploration of Privileged Warheads for Covalent Kinase Drug Discovery |
| title_sort | systematic exploration of privileged warheads for covalent kinase drug discovery |
| topic | kinase inhibitor covalent kinase inhibitor privileged warhead nucleophile rational drug discovery |
| url | https://www.mdpi.com/1424-8247/15/11/1322 |
| work_keys_str_mv | AT zhengzhao systematicexplorationofprivilegedwarheadsforcovalentkinasedrugdiscovery AT philipebourne systematicexplorationofprivilegedwarheadsforcovalentkinasedrugdiscovery |