DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance
Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been util...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44237-4 |
| _version_ | 1827139287659839488 |
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| author | Martin Schröder Martin Renatus Xiaoyou Liang Fabian Meili Thomas Zoller Sandrine Ferrand Francois Gauter Xiaoyan Li Frederic Sigoillot Scott Gleim Therese-Marie Stachyra Jason R. Thomas Damien Begue Maryam Khoshouei Peggy Lefeuvre Rita Andraos-Rey BoYee Chung Renate Ma Benika Pinch Andreas Hofmann Markus Schirle Niko Schmiedeberg Patricia Imbach Delphine Gorses Keith Calkins Beatrice Bauer-Probst Magdalena Maschlej Matt Niederst Rob Maher Martin Henault John Alford Erik Ahrne Luca Tordella Greg Hollingworth Nicolas H. Thomä Anna Vulpetti Thomas Radimerski Philipp Holzer Seth Carbonneau Claudio R. Thoma |
| author_facet | Martin Schröder Martin Renatus Xiaoyou Liang Fabian Meili Thomas Zoller Sandrine Ferrand Francois Gauter Xiaoyan Li Frederic Sigoillot Scott Gleim Therese-Marie Stachyra Jason R. Thomas Damien Begue Maryam Khoshouei Peggy Lefeuvre Rita Andraos-Rey BoYee Chung Renate Ma Benika Pinch Andreas Hofmann Markus Schirle Niko Schmiedeberg Patricia Imbach Delphine Gorses Keith Calkins Beatrice Bauer-Probst Magdalena Maschlej Matt Niederst Rob Maher Martin Henault John Alford Erik Ahrne Luca Tordella Greg Hollingworth Nicolas H. Thomä Anna Vulpetti Thomas Radimerski Philipp Holzer Seth Carbonneau Claudio R. Thoma |
| author_sort | Martin Schröder |
| collection | DOAJ |
| description | Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings. |
| first_indexed | 2024-03-08T16:16:28Z |
| format | Article |
| id | doaj.art-8f2eff537f564b01931321a688bb396a |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2025-03-20T18:36:51Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8f2eff537f564b01931321a688bb396a2024-08-25T11:26:32ZengNature PortfolioNature Communications2041-17232024-01-0115111910.1038/s41467-023-44237-4DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistanceMartin Schröder0Martin Renatus1Xiaoyou Liang2Fabian Meili3Thomas Zoller4Sandrine Ferrand5Francois Gauter6Xiaoyan Li7Frederic Sigoillot8Scott Gleim9Therese-Marie Stachyra10Jason R. Thomas11Damien Begue12Maryam Khoshouei13Peggy Lefeuvre14Rita Andraos-Rey15BoYee Chung16Renate Ma17Benika Pinch18Andreas Hofmann19Markus Schirle20Niko Schmiedeberg21Patricia Imbach22Delphine Gorses23Keith Calkins24Beatrice Bauer-Probst25Magdalena Maschlej26Matt Niederst27Rob Maher28Martin Henault29John Alford30Erik Ahrne31Luca Tordella32Greg Hollingworth33Nicolas H. Thomä34Anna Vulpetti35Thomas Radimerski36Philipp Holzer37Seth Carbonneau38Claudio R. Thoma39Novartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchFriedrich Miescher Institute for Biomedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchNovartis Institutes for BioMedical ResearchAbstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.https://doi.org/10.1038/s41467-023-44237-4 |
| spellingShingle | Martin Schröder Martin Renatus Xiaoyou Liang Fabian Meili Thomas Zoller Sandrine Ferrand Francois Gauter Xiaoyan Li Frederic Sigoillot Scott Gleim Therese-Marie Stachyra Jason R. Thomas Damien Begue Maryam Khoshouei Peggy Lefeuvre Rita Andraos-Rey BoYee Chung Renate Ma Benika Pinch Andreas Hofmann Markus Schirle Niko Schmiedeberg Patricia Imbach Delphine Gorses Keith Calkins Beatrice Bauer-Probst Magdalena Maschlej Matt Niederst Rob Maher Martin Henault John Alford Erik Ahrne Luca Tordella Greg Hollingworth Nicolas H. Thomä Anna Vulpetti Thomas Radimerski Philipp Holzer Seth Carbonneau Claudio R. Thoma DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance Nature Communications |
| title | DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance |
| title_full | DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance |
| title_fullStr | DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance |
| title_full_unstemmed | DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance |
| title_short | DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance |
| title_sort | dcaf1 based protacs with activity against clinically validated targets overcoming intrinsic and acquired degrader resistance |
| url | https://doi.org/10.1038/s41467-023-44237-4 |
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