Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 144, Issue 28, Pages 12934-12941Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c04824
Keywords
-
Categories
Funding
- NIH [R35CA253027, P30CA196521]
- National Institutes of Health SIG [1S10OD02 5132, 1S10OD028504]
- Icahn School of Medicine at Mount Sinai
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available