한빛사 논문
Yeongju Lee,[a] Jiwon Heo,[b] Hoibin Jeong,[c] Kyung Tae Hong,[d] Do Hoon Kwon,[b] Min Hyeon Shin,[a] Misook Oh,[a] Ganesh A. Sable,[a] G-One Ahn,*[c] Jun-Seok Lee,*[d] Hyun Kyu Song,*[b] and Hyun-Suk Lim*[a]
[a] 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
[b] School of Life Sciences and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, South Korea
[c] Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, South Korea
[d] Molecular Recognition Research Center, Korea Institute of Science and Technology (KIST), 5. Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 02792, South Korea
*Corresponding author
Abstract
Aberrantly elevated steroid receptor co‐activator‐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.
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