期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 144, 期 28, 页码 12934-12941出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c04824
关键词
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资金
- NIH [R35CA253027, P30CA196521]
- National Institutes of Health SIG [1S10OD02 5132, 1S10OD028504]
- Icahn School of Medicine at Mount Sinai
A platform named TF-DUBTAC has been developed to selectively stabilize tumor suppressor transcription factors through linking a DNA oligonucleotide to a covalent ligand of the deubiquitinase OTUB1. This method successfully stabilized FOXO3A, p53, and IRF3 in cells, providing a potential therapeutic means to suppress tumorigenesis.
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 IRFDUBTAC, 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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