A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation
Abstract Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein, which functions as an RNA regulator. Overexpression of HuR correlates with high grade tumours and poor patient prognosis, implicating it as an attractive therapeutic target. However, an effective small molecule antagonis...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42546-2 |
| _version_ | 1827770418220498944 |
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| author | Alice Fletcher Dean Clift Emma de Vries Sergio Martinez Cuesta Timothy Malcolm Francesco Meghini Raghothama Chaerkady Junmin Wang Abby Chiang Shao Huan Samuel Weng Jonathan Tart Edmond Wong Gerard Donohoe Philip Rawlins Euan Gordon Jonathan D. Taylor Leo James James Hunt |
| author_facet | Alice Fletcher Dean Clift Emma de Vries Sergio Martinez Cuesta Timothy Malcolm Francesco Meghini Raghothama Chaerkady Junmin Wang Abby Chiang Shao Huan Samuel Weng Jonathan Tart Edmond Wong Gerard Donohoe Philip Rawlins Euan Gordon Jonathan D. Taylor Leo James James Hunt |
| author_sort | Alice Fletcher |
| collection | DOAJ |
| description | Abstract Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein, which functions as an RNA regulator. Overexpression of HuR correlates with high grade tumours and poor patient prognosis, implicating it as an attractive therapeutic target. However, an effective small molecule antagonist to HuR for clinical use remains elusive. Here, a single domain antibody (VHH) that binds HuR with low nanomolar affinity was identified and shown to inhibit HuR binding to RNA. This VHH was used to engineer a TRIM21-based biological PROTAC (bioPROTAC) that could degrade endogenous HuR. Significantly, HuR degradation reverses the tumour-promoting properties of cancer cells in vivo by altering the HuR-regulated proteome, highlighting the benefit of HuR degradation and paving the way for the development of HuR-degrading therapeutics. These observations have broader implications for degrading intractable therapeutic targets, with bioPROTACs presenting a unique opportunity to explore targeted-protein degradation through a modular approach. |
| first_indexed | 2024-03-11T12:39:17Z |
| format | Article |
| id | doaj.art-0a4a30a2a8bb41ef8d8998148778ebbb |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-11T12:39:17Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-0a4a30a2a8bb41ef8d8998148778ebbb2023-11-05T12:23:06ZengNature PortfolioNature Communications2041-17232023-11-0114111410.1038/s41467-023-42546-2A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradationAlice Fletcher0Dean Clift1Emma de Vries2Sergio Martinez Cuesta3Timothy Malcolm4Francesco Meghini5Raghothama Chaerkady6Junmin Wang7Abby Chiang8Shao Huan Samuel Weng9Jonathan Tart10Edmond Wong11Gerard Donohoe12Philip Rawlins13Euan Gordon14Jonathan D. Taylor15Leo James16James Hunt17Biologics Engineering, R&D, AstraZenecaMRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical CampusBiologics Engineering, R&D, AstraZenecaData Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZenecaBiologics Engineering, R&D, AstraZenecaBiologics Engineering, R&D, AstraZenecaCentre for Genomics Research, Discovery Sciences, R&D, AstraZenecaCentre for Genomics Research, Discovery Sciences, R&D, AstraZenecaCentre for Genomics Research, Discovery Sciences, R&D, AstraZenecaCentre for Genomics Research, Discovery Sciences, R&D, AstraZenecaDiscovery Biology, Discovery Sciences, R&D, AstraZenecaBiologics Engineering, R&D, AstraZenecaBiologics Engineering, R&D, AstraZenecaMechanistic and Structural Biology, Discovery Sciences, R&D, AstraZenecaDiscovery Biology, Discovery Sciences, R&D, AstraZenecaBiologics Engineering, R&D, AstraZenecaMRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical CampusBiologics Engineering, R&D, AstraZenecaAbstract Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein, which functions as an RNA regulator. Overexpression of HuR correlates with high grade tumours and poor patient prognosis, implicating it as an attractive therapeutic target. However, an effective small molecule antagonist to HuR for clinical use remains elusive. Here, a single domain antibody (VHH) that binds HuR with low nanomolar affinity was identified and shown to inhibit HuR binding to RNA. This VHH was used to engineer a TRIM21-based biological PROTAC (bioPROTAC) that could degrade endogenous HuR. Significantly, HuR degradation reverses the tumour-promoting properties of cancer cells in vivo by altering the HuR-regulated proteome, highlighting the benefit of HuR degradation and paving the way for the development of HuR-degrading therapeutics. These observations have broader implications for degrading intractable therapeutic targets, with bioPROTACs presenting a unique opportunity to explore targeted-protein degradation through a modular approach.https://doi.org/10.1038/s41467-023-42546-2 |
| spellingShingle | Alice Fletcher Dean Clift Emma de Vries Sergio Martinez Cuesta Timothy Malcolm Francesco Meghini Raghothama Chaerkady Junmin Wang Abby Chiang Shao Huan Samuel Weng Jonathan Tart Edmond Wong Gerard Donohoe Philip Rawlins Euan Gordon Jonathan D. Taylor Leo James James Hunt A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation Nature Communications |
| title | A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation |
| title_full | A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation |
| title_fullStr | A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation |
| title_full_unstemmed | A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation |
| title_short | A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation |
| title_sort | trim21 based bioprotac highlights the therapeutic benefit of hur degradation |
| url | https://doi.org/10.1038/s41467-023-42546-2 |
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