Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway

Yeongju Lee, Jiwon Heo, Hoibin Jeong, Kyung Tae Hong, Do Hoon Kwon, Min Hyeon Shin, Misook Oh, Ganesh A. Sable, G. One Ahn, Jun Seok Lee, Hyun Kyu Song, Hyun Suk Lim

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17548-17555
Number of pages8
JournalAngewandte Chemie - International Edition
Volume59
Issue number40
DOIs
StatePublished - Sep 28 2020

Keywords

  • SRC-1 transcriptional co-activator
  • cancer metastasis
  • proteolysis-targeting chimers (PROTACs)
  • stapled peptide
  • the N-degron pathway

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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