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Targeted Degradation of Transcription Coactivator SRC‐1 through the N‐Degron Pathway
Author(s) -
Lee Yeongju,
Heo Jiwon,
Jeong Hoibin,
Hong Kyung Tae,
Kwon Do Hoon,
Shin Min Hyeon,
Oh Misook,
Sable Ganesh A.,
Ahn GOne,
Lee JunSeok,
Song Hyun Kyu,
Lim HyunSuk
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202005004
Subject(s) - degron , coactivator , proto oncogene tyrosine protein kinase src , microbiology and biotechnology , proteolysis , chemistry , ubiquitin , protein degradation , biology , cancer research , transcription factor , ubiquitin ligase , biochemistry , signal transduction , gene , enzyme
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.