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

Angew Chem Int Ed Engl. 2020 Sep 28;59(40):17548-17555. doi: 10.1002/anie.202005004. Epub 2020 Aug 12.

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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, CD / metabolism
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biocatalysis
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Down-Regulation / drug effects
  • Humans
  • Macrophage Colony-Stimulating Factor / metabolism
  • Mice, Inbred BALB C
  • Neoplasm Invasiveness / prevention & control
  • Neoplasms / drug therapy
  • Nuclear Receptor Coactivator 1 / antagonists & inhibitors*
  • Nuclear Receptor Coactivator 1 / metabolism
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Protein Binding
  • Signal Transduction / drug effects
  • Ubiquitin-Protein Ligases / metabolism*
  • Up-Regulation / drug effects

Substances

  • Antigens, CD
  • Antineoplastic Agents
  • CDH1 protein, human
  • CSF1 protein, human
  • Cadherins
  • Peptides
  • Macrophage Colony-Stimulating Factor
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1
  • Ubiquitin-Protein Ligases