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

Resultado de la investigación: Articlerevisión exhaustiva

11 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)15172-15175
Número de páginas4
PublicaciónJournal of Biological Chemistry
Volumen294
N.º41
DOI
EstadoPublished - oct. 11 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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