Lee, Yeongju Heo, Jiwon Jeong, Hoibin Hong, Kyung Tae Kwon, Do Hoon Shin, Min Hyeon Oh, Misook Sable, Ganesh A. Ahn, G-One Lee, Jun-Seok Song, Hyun Kyu Lim, Hyun-Suk 2024-01-19T16:33:01Z 2024-01-19T16:33:01Z 2021-09-02 2020-09-28 1433-7851 https://pubs.kist.re.kr/handle/201004/118094 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. English John Wiley & Sons Ltd. STEROID-RECEPTOR COACTIVATOR-1 END RULE PATHWAY PROTEIN COMPLEX INHIBITION ACTIVATION STAT6 COREGULATORS RECOGNITION EXPRESSION Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway Article 10.1002/anie.202005004 1 Angewandte Chemie International Edition, v.59, no.40, pp.17548 - 17555 Angewandte Chemie International Edition 59 40 17548 17555 scie scopus 000558478500001 2-s2.0-85089311954 Chemistry, Multidisciplinary Chemistry Article STEROID-RECEPTOR COACTIVATOR-1 END RULE PATHWAY PROTEIN COMPLEX INHIBITION ACTIVATION STAT6 COREGULATORS RECOGNITION EXPRESSION cancer metastasis proteolysis-targeting chimers (PROTACs) SRC-1 transcriptional co-activator stapled peptide the N-degron pathway