Targeted protein degradation: expanding the toolbox
Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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Nature Research
2019
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| _version_ | 1797075486239621120 |
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| author | Schapira, M Calabrese, M Bullock, A Crews, C |
| author_facet | Schapira, M Calabrese, M Bullock, A Crews, C |
| author_sort | Schapira, M |
| collection | OXFORD |
| description | Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery. |
| first_indexed | 2024-03-06T23:50:56Z |
| format | Journal article |
| id | oxford-uuid:7291c51e-b058-4f99-87c6-3085ed467c2e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:50:56Z |
| publishDate | 2019 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:7291c51e-b058-4f99-87c6-3085ed467c2e2022-03-26T19:50:56ZTargeted protein degradation: expanding the toolboxJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7291c51e-b058-4f99-87c6-3085ed467c2eEnglishSymplectic Elements at OxfordNature Research2019Schapira, MCalabrese, MBullock, ACrews, CProteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery. |
| spellingShingle | Schapira, M Calabrese, M Bullock, A Crews, C Targeted protein degradation: expanding the toolbox |
| title | Targeted protein degradation: expanding the toolbox |
| title_full | Targeted protein degradation: expanding the toolbox |
| title_fullStr | Targeted protein degradation: expanding the toolbox |
| title_full_unstemmed | Targeted protein degradation: expanding the toolbox |
| title_short | Targeted protein degradation: expanding the toolbox |
| title_sort | targeted protein degradation expanding the toolbox |
| work_keys_str_mv | AT schapiram targetedproteindegradationexpandingthetoolbox AT calabresem targetedproteindegradationexpandingthetoolbox AT bullocka targetedproteindegradationexpandingthetoolbox AT crewsc targetedproteindegradationexpandingthetoolbox |