A modular PROTAC design for target destruction using a degradation signal based on a single amino acid

Karthigayan Shanmugasundaram, Peng Shao, Han Chen, Bismarck Campos, Stanton F. McHardy, Tuoping Luo, Hai Rao

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Proteolysis targeting chimeras (PROTACs) are bivalent molecules that bring a cellular protein to a ubiquitin ligase E3 for ubiquitination and subsequent degradation. Although PROTAC has emerged as a promising therapeutic means for cancers as it rewires the ubiquitin pathway to destroy key cancer regulators, the degradation signals/pathways for PROTACs remain underdeveloped. Here we append single amino acids, the simplest degradation signal, to a ligand specific for estrogen-related receptor (ERR) and demonstrate their utility in ERR knockdown via the N-end rule pathway and also their efficiency in the growth inhibition of breast cancer cells. The modular design described offers unique advantages including smaller molecular size with shortest degradation sequences and degradation speed modulation with different amino acids. Our study expands the repertoire of limited ubiquitin pathways currently available for PROTACs and could be easily adapted for broad use in targeted protein degradation.

Original languageEnglish (US)
Pages (from-to)15172-15175
Number of pages4
JournalJournal of Biological Chemistry
Volume294
Issue number41
DOIs
StatePublished - Oct 11 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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