Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules
Open accessPreprint — published as 10.1038/s41467-020-18377-w · Paper page
Abstract
Chemical biology strategies for directly perturbing protein homeostasis including the degradation tag (dTAG) system provide temporal advantages over genetic approaches and improved selectivity over small molecule inhibitors. We describe dTAG V -1, an exclusively selective VHL-recruiting dTAG molecule, to rapidly degrade FKBP12 F36V -tagged proteins. dTAG V -1 overcomes a limitation of previously reported CRBN-recruiting dTAG molecules to degrade recalcitrant oncogenes, supports combination degrader studies and facilitates investigations of protein function in cells and mice.
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Nabet et al. developed a heterologous tagging platform, dTAG, that allows validation of unliganded or yet-to-be-liganded proteins as degradation targets and is enabled for both VHL and CRBN.
“Nabet et al.53,95 have developed a heterologous tagging platform, dTAG, that allows validation of unliganded or yet-to-be-liganded proteins as degradation targets and is enabled for both VHL and CRBN.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [95]
CARs fused to an additional domain allowing for PROTAC-mediated degradation have been designed as a reversible chemical safety switch.
“CARs fused to an additional domain allowing for PROTAC-mediated degradation have been designed as a reversible chemical safety switch203.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [203]
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- Authors
- Nabet, B., Ferguson, F. M., Seong, B. K. A., Kuljanin, M., Leggett, A. L., Mohardt, M. L., Robichaud, A., Conway, A. S., Buckley, D. L., Mancias, J. D., Bradner, J. E., Stegmaier, K., & Gray, N. S.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Nabet, Behnam
- Gray, Nathanael S.
- ORCID
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2020-03-16
- Volume
- 11
- Issue
- 1
- Pages
- 4687-4687
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W3087526660
- Cited by
- 312
- References
- 50
- Citations by year
- 2026: 58 · 2025: 74 · 2024: 68 · 2023: 41 · 2022: 38 · 2021: 28 · 2020: 4
- FWCI
- 9.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Defense (CA181249)
- U.S. Department of Health and Human Services (CA231637, CA204915)
- American Cancer Society (PF-17-010-01-CDD)
- Damon Runyon Cancer Research Foundation (DRG219614)
- National Institutes of Health (3u54ca231637-01s2)
- National Cancer Institute (CA231637, U54-CA231637, CA204915, R01CA204915)
- DOD Peer Reviewed Cancer Research Program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- VHL, cereblon, protein degradation, proteostasis
- MeSH terms
- Animals, Female, Humans, Male, Mice, Inbred C57BL, Peptide Hydrolases, Proteins, Proto-Oncogene Proteins p21(ras), Mice, Inbred NOD, Mice, Knockout, Tacrolimus Binding Proteins, Tacrolimus Binding Protein 1A, Models, Animal, Proteomics, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Gene Knockout Techniques, HEK293 Cells
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