HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins
Open accessAbstract
Small molecule-induced protein degradation is an attractive strategy for the development of chemical probes. One method for inducing targeted protein degradation involves the use of PROTACs, heterobifunctional molecules that can recruit specific E3 ligases to a desired protein of interest. PROTACs have been successfully used to degrade numerous proteins in cells, but the peptidic E3 ligase ligands used in previous PROTACs have hindered their development into more mature chemical probes or therapeutics. We report the design of a novel class of PROTACs that incorporate small molecule VHL ligands to successfully degrade HaloTag7 fusion proteins. These HaloPROTACs will inspire the development of future PROTACs with more drug-like properties. Additionally, these HaloPROTACs are useful chemical genetic tools, due to their ability to chemically knock down widely used HaloTag7 fusion proteins in a general fashion.
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Buckley et al. developed a tagging system based on HaloTag fusions that can be targeted by HaloPROTACs.
“Buckley et al.94 have developed a tagging system based on HaloTag fusions that can be targeted by HaloPROTACs”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [94]
AP1867 and FKBP12F36V are a bump-and-hole engineered small molecule-protein pair orthogonal to rapamycin and wild-type FKBP12.
“AP1867 and FKBP12F36V are a bump-and-hole engineered small molecule–protein pair orthogonal to rapamycin and wild-type FKBP12202.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [202]
Tag-specific PROTACs such as HaloPROTACs and dTAG-13 offer opportunities for inducible degradation of POIs by using tag-specific PROTACs.
“Therefore, moieties that recognize polypeptide tags, such as HALO and dTAG that could be inserted into POIs by CRISPR/Cas9 genome editing, offer opportunities for inducible degradation of POIs by using the tag-specific PROTACs (such as HaloPROTACs and dTAG-13, respectively) [108, 109].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [109]
HaloPROTACs bind to the HALO tag on POIs on one side and VHL on the other, and have been successfully employed to rapidly and inducibly degrade HALO-tagged POIs through the VHL/CUL2/RBX1-dependent UPS.
“HaloPROTACs, which bind to the HALO tag on POIs on one side and VHL on the other, have been successfully employed to rapidly and inducibly degrade HALO-tagged POIs through the VHL/CUL2/RBX1-dependent UPS [109].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [109]
The HALO tag has an apparent large size of approximately 33 kDa.
“However, one of the limitations of using the HALO tag is its apparent large size (~ 33 kDa).”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [109]
Saturating doses of free PROTAC molecules can antagonize the binding of binary PROTAC-protein complexes to their ternary partner and abrogate catalytic degradation, a phenomenon known as the hook effect in cell assays.
“Regarding clinical applications, appropriate dosage may be an issue, as saturating doses of free PROTAC molecules can antagonize the binding of binary PROTAC-protein complexes to their ternary partner and abrogate catalytic degradation, a well-documented phenomenon known as the hook effect in cell assays 23,33,34 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [34]
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- Authors
- Buckley, D. L., Raina, K., Darricarrere, N., Hines, J., Gustafson, J. L., Smith, I. E., Miah, A. H., Harling, J. D., & Crews, C. M.
- Affiliations
- GlaxoSmithKline (United Kingdom) (GB)
- Corresponding author
- Crews, Craig M.
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-06-23
- Volume
- 10
- Issue
- 8
- Pages
- 1831-1837
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- PMC
- PMC4629848
- OpenAlex
- W2292464399
- Cited by
- 488
- References
- 38
- Citations by year
- 2026: 54 · 2025: 63 · 2024: 60 · 2023: 44 · 2022: 58 · 2021: 61 · 2020: 50 · 2019: 35 · 2018: 24 · 2017: 23 · 2016: 11 · 2015: 4
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI084140)
- Congressionally Directed Medical Research Programs (W81XWH-12-1-0484)
- National Institute of General Medical Sciences (F32GM10052101)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, targeted protein degradation, chemical probes, chemical genetics, protein degradation, heterobifunctional molecules
- MeSH terms
- Humans, Ligands, Protein Binding, Recombinant Fusion Proteins, Ubiquitin-Protein Ligases, Small Molecule Libraries, HEK293 Cells, Proteolysis
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