TF-PROTACs Enable Targeted Degradation of Transcription Factors
Open accessAbstract
Transcription factors (TFs) represent a major class of therapeutic targets for the treatment of human diseases including cancer. Although the biological functions and even crystal structures of many TFs have been clearly elucidated, there is still no viable approach to target the majority of TFs, thus rendering them undruggable for decades. PROTACs (proteolysis targeting chimeras) emerge as a powerful class of therapeutic modalities, which rely on induced protein-protein interactions between the proteins of interest (POIs) and E3 ubiquitin ligases to aid the degradation of POIs by the ubiquitin-proteasome system (UPS). Here, we report the development of a platform termed TF-PROTAC, which links an DNA oligonucleotide to an E3 ligase ligand via a click reaction, to selectively degrade the TF of interest. The selectivity of these TF-PROTACs depends on the DNA oligonucleotides utilized that can be specific to the TFs of interest. We have developed two series of VHL-based TF-PROTACs, NF-κB-PROTAC (dNF-κB) and E2F-PROTAC (dE2F), which effectively degrade endogenous p65 and E2F1 proteins in cells, respectively, and subsequently display superior antiproliferative effects in cells. Collectively, our results suggest that TF-PROTACs provide a generalizable platform to achieve selective degradation of TFs and a universal strategy for targeting most "undruggable" TFs.
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PROTAC technology has been widely used to specifically flag transcription factors for degradation.
“Proteolysis targeting chimeric (PROTAC) technology has been widely used to specifically flag transcription factors for degradation (22).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [22]
The Introduction describes PROTACs as suitable for targeting transcription factors, and the Conclusion reports proof-of-concept TF-PROTACs that degraded p65 and E2F1 in cells. The paper does not establish that PROTAC technology has been widely used to degrade transcription factors; it presents this application as a developing approach. (LLM, conf=0.88)
Experimental — accuracy not yet measuredO'PROTACs and transcription factor PROTACs use a double-stranded DNA consensus sequence as the transcription factor-binding warhead, linked to an E3 ligase-recruiting ligand.
“Similarly, O’PROTACs221 and transcription factor PROTACs222 use a double-stranded DNA (dsDNA) consensus sequence as the transcription factor-binding warhead, linked to an E3 ligase-recruiting ligand.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [222]
Such constructs have been shown to reduce levels of the RBP LIN28A and the transcription factors ERG and LEF1 in various human cancer cell lines.
“Such constructs have been shown to reduce levels of the RBP LIN28A and the transcription factors ETS transcription factor (ERG) and lymphoid enhancer-binding factor 1 (LEF1) in various human cancer cell lines.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [222]
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ARE-PROTACs Enable Co-degradation of an Nrf2–MafG Heterodimer
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Development of miRNA-based PROTACs targeting Lin28 for breast cancer therapy
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Beyond canonical PROTAC: biological targeted protein degradation (bioTPD)
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Past, Current, and Future Strategies to Target ERG Fusion-Positive Prostate Cancer
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Unconventional PROTACs for Targeted Protein Degradation in Cancer Therapy
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Self-citationTargeted Protein Degradation Technology and Nanomedicine: Powerful Allies against Cancer
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Self-citationTargeted protein degradation: current molecular targets, localization, and strategies
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PROTAC Degrader of Estrogen Receptor α Targeting DNA-Binding Domain in Breast Cancer
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PROTACs: Current Trends in Protein Degradation by Proteolysis-Targeting Chimeras
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Deubiquitinase-Targeting Chimeras (DUBTACs) as a Potential Paradigm-Shifting Drug Discovery Approach
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USP28-Based Deubiquitinase-Targeting Chimeras for Cancer Treatment
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USP7-Based Deubiquitinase-Targeting Chimeras Stabilize AMPK
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Self-citationFrom PROTAC to TPD: Advances and Opportunities in Targeted Protein Degradation
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Targeted Protein Degradation: Clinical Advances in the Field of Oncology
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Telomere Targeting Chimera Enables Targeted Destruction of Telomeric Repeat-Binding Factor Proteins
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Self-citationRIPTACs: A groundbreaking approach to drug discovery
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PROTACs in the Management of Prostate Cancer
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DNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases
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PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas
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O-GlcNAcylation in tumorigenesis and its implications for cancer therapy
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Self-citationPROTAC Technology as a New Tool for Modern Pharmacotherapy
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Transcription Factors and Cancer
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Development of DNA Aptamer-Based PROTACs That Degrade the Estrogen Receptor
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- Authors
- Liu, J., 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
- 2021-06-08
- Volume
- 143
- Issue
- 23
- Pages
- 8902-8910
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC8225582
- OpenAlex
- W3167977328
- Cited by
- 247
- References
- 42
- Citations by year
- 2026: 35 · 2025: 55 · 2024: 48 · 2023: 52 · 2022: 50 · 2021: 6
- FWCI
- 12.56
- 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, R01CA218600, R01CA230854, R01CA260666, R35CA253027)
- National Institute of General Medical Sciences (R01GM122749)
- 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
- PROTACs, transcription factor degradation, undruggable targets, VHL E3 ubiquitin ligase, NF-κB p65, E2F1, click chemistry, ubiquitin-proteasome system, targeted protein degradation, antiproliferative activity
- MeSH terms
- HeLa Cells, Humans, Ligands, Molecular Conformation, Transcription Factors, Proteolysis
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