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.
Original language | English |
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Pages (from-to) | 17548-17555 |
Number of pages | 8 |
Journal | Angewandte Chemie - International Edition |
Volume | 59 |
Issue number | 40 |
DOIs | |
Publication status | Published - 2020 Sept 28 |
Bibliographical note
Publisher Copyright:© 2020 Wiley-VCH GmbH
Keywords
- SRC-1 transcriptional co-activator
- cancer metastasis
- proteolysis-targeting chimers (PROTACs)
- stapled peptide
- the N-degron pathway
ASJC Scopus subject areas
- Catalysis
- General Chemistry