TF-DUBTACs Stabilize Tumor Suppressor Transcription Factors
Open accessAbstract
Targeted protein degradation approaches have been widely used for degrading oncogenic proteins, providing a potentially promising therapeutic strategy for cancer treatment. However, approaches to targeting tumor suppressor proteins are very limited, and only a few agonists have been developed to date. Here, we report the development of a platform termed TF-DUBTAC, which links a DNA oligonucleotide to a covalent ligand of the deubiquitinase OTUB1 via a click reaction, to selectively stabilize tumor suppressor transcription factors. We developed three series of TF-DUBTACs, namely, FOXO-DUBTAC, p53-DUBTAC, and IRF-DUBTAC, which stabilize FOXO3A, p53, and IRF3 in cells, respectively, in an OTUB1-dependent manner. These results suggest that TF-DUBTAC is a generalizable platform to achieve selective stabilization of tumor suppressor transcription factors as a therapeutic means to suppress tumorigenesis.
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Compound 233 significantly upregulated FOXO3A in a concentration-dependent manner and selectively stabilized FOXO3A compared with the structurally similar FOX1 within the same family.
“They discovered that compound 233 significantly upregulated FOXO3A in a concentration-dependent manner, exhibiting selective stabilization of FOXO3A compared to the structurally similar FOX1 within the same family (Table 4).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [549]
Wei's team developed a TF-DUBTAC platform capable of selectively stabilizing oncoproteins including FOXO3A, p53, and IRF3.
“Wei’s team developed a TF-DUBTAC platform capable of selectively stabilizing oncoproteins, including FOXO3A, p53, and IRF3.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [549]
Unbiased mass spectrometry analysis revealed that compound 6 efficiently and specifically stabilized FOXO3A while inhibiting Myc expression.
“Unbiased mass spectrometry analysis revealed that compound 6 efficiently and specifically stabilized FOXO3A while inhibiting Myc expression, demonstrating its potential as a promising therapeutic approach.549”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [549]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Liu, J., Yu, X., Chen, H., Kaniskan, H. Ü., Xie, L., Chen, X., Jin, J., & Wei, W.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Tisch Cancer Institute (US)
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Jin, Jian
- Wei, Wenyi
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-07-05
- Volume
- 144
- Issue
- 28
- Pages
- 12934-12941
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC10981454
- OpenAlex
- W4283836349
- Cited by
- 73
- References
- 49
- Citations by year
- 2026: 20 · 2025: 19 · 2024: 16 · 2023: 15 · 2022: 2 · 2014: 1
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA196521, R35CA253027)
- Icahn School of Medicine at Mount Sinai
- 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
- targeted protein degradation, OTUB1, deubiquitinase, protein stabilization, FOXO3, p53, IRF3, DNA oligonucleotides, covalent ligands, click chemistry, cancer therapy
- MeSH terms
- Humans, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Proteolysis, Carcinogenesis
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