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Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway
Cited 22 time in
Web of Science
Cited 21 time in Scopus
- Authors
- Issue Date
- 2020-09
- Publisher
- John Wiley & Sons Ltd.
- Citation
- Angewandte Chemie - International Edition, Vol.59 No.40, pp.17548-17555
- Abstract
- Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through the N-degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC-1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC-1 degrader can be an invaluable chemical tool in the studies of SRC-1 functions. Moreover, our findings suggest PROTACs based on the N-degron pathway as a widely useful strategy to degrade disease-relevant proteins.
- ISSN
- 1433-7851
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