Targeted Degradation of Transcription Coactivator SRC‐1 through the N‐Degron Pathway
| Autor: | 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 |
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| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | Angewandte Chemie International Edition. 59:17548-17555 |
| ISSN: | 1521-3773 1433-7851 |
| DOI: | 10.1002/anie.202005004 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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