Destruction of DNA-binding proteins by programmable O’PROTAC: Oligonucleotide-based PROTAC
Open accessAbstract
DNA-binding proteins including transcription factors (TFs) play essential roles in gene transcription and DNA replication and repair during normal organ development and pathogenesis of diseases such as cancer, cardiovascular disease and obesity, deeming to be a large repertoire of attractive therapeutic targets. However, this group of proteins are generally considered undruggable as they lack an enzymatic catalytic site or a ligand binding pocket. PROteolysis-TArgeting Chimera (PROTAC) technology has been developed by engineering a bifunctional small molecule chimera to bring a protein of interest (POI) to the proximity of an E3 ubiquitin ligase, thus inducing the ubiquitination of POI and further degradation through proteasome pathway. Here we report the development of Oligonucleotide-based PROTAC (O’PROTACs), a class of noncanonical PROTACs in which a TF-recognizing double-stranded oligonucleotide is incorporated as a binding moiety of POI. We demonstrate that O’PROTACs of ERG and LEF1, two highly cancer-related transcription factors selectively promote degradation of these proteins and inhibit their transcriptional activity in cancer cells. The programmable nature of O’PROTACs indicates that this approach is applicable to destruct other TFs. O’PROTACs not only can serve as a research tool, but also can be harnessed as a therapeutic arsenal to target DNA binding proteins for effective treatment of diseases such as cancer.
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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 [221]
O'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 [221]
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References 34 · Cited by 2
- Authors
- Shao, J., Yan, Y., Ding, D., Wang, D., He, Y., Pan, Y., Yan, W., Kharbanda, A., Li, H.-Y., & Huang, H.
- Affiliations
- University of Arkansas for Medical Sciences (US)
- Mayo Clinic (US)
- Corresponding author
- Huang, Haojie
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2021-03-09
- OpenAlex
- W3134947967
- Cited by
- 2
- References
- 34
- Citations by year
- 2022: 1 · 2021: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- 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, DNA-binding proteins, transcription factors, ERG, LEF1, protein degradation, E3 ubiquitin ligase, ubiquitination, proteasome, cancer therapy, undruggable targets
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