Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway
- Angew Chem Int Ed Engl. 2020 Sep 28;59(40):17548-17555. doi: 10.1002/anie.202005004.
- 1. Department of Chemistry and Division of Advanced Materials Science, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-Gu, Pohang, 37673, South Korea.
- 2. School of Life Sciences and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, South Korea.
- 3. Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea.
- 4. Molecular Recognition Research Center, Korea Institute of Science and Technology (KIST), 5. Hwarang-ro, 14-gil, Seongbuk-gu, Seoul, 02792, South Korea.
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.