Targeted Degradation of Transcription Coactivator SRC‐1 through the N‐Degron Pathway
| العنوان: | Targeted Degradation of Transcription Coactivator SRC‐1 through the N‐Degron Pathway |
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| المؤلفون: | Kyung Tae Hong, Do Hoon Kwon, Hyun-Suk Lim, Min Hyeon Shin, Jiwon Heo, Hoibin Jeong, Jun-Seok Lee, Misook Oh, G-One Ahn, Hyun Kyu Song, Yeongju Lee, Ganesh A. Sable |
| المصدر: | Angewandte Chemie International Edition. 59:17548-17555 |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Cell type, Ubiquitin-Protein Ligases, Down-Regulation, Antineoplastic Agents, 010402 general chemistry, 01 natural sciences, Catalysis, Nuclear Receptor Coactivator 1, Antigens, CD, Cell Movement, Cell Line, Tumor, Neoplasms, Animals, Humans, Neoplasm Invasiveness, Amino Acid Sequence, Receptor, Mice, Inbred BALB C, 010405 organic chemistry, Chemistry, Macrophage Colony-Stimulating Factor, Proteolysis targeting chimera, General Medicine, General Chemistry, Cadherins, Ligand (biochemistry), Up-Regulation, 0104 chemical sciences, Cell biology, Transcription Coactivator, Cancer cell, Biocatalysis, Degron, Peptides, Protein Binding, Signal Transduction, Proto-oncogene tyrosine-protein kinase Src |
| الوصف: | 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. |
| تدمد: | 1521-3773 1433-7851 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::051d54dd76ed568e9449e82ffd3244ac https://doi.org/10.1002/anie.202005004 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....051d54dd76ed568e9449e82ffd3244ac |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15213773 14337851 |
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