Design and synthesis of peptide-based chimeric molecules to induce degradation of the estrogen and androgen receptors

Bioorg Med Chem. 2020 Aug 1;28(15):115595. doi: 10.1016/j.bmc.2020.115595. Epub 2020 Jun 12.


Peptide-based inducers of estrogen receptor (ER) α and androgen receptor (AR) degradations via the ubiquitin-proteasome system (UPS) were developed. The designated inducers were composed of two biologically active scaffolds: the helical peptide PERM3, which is an LXXLL-like mimic of the coactivator SRC-1, and various small molecules (MV1, LCL161, VH032, and POM) that bind to E3 ligases (IAPs, VHL, and cereblon, respectively), to induce ubiquitylation of nuclear receptors that bind to SRC-1. All of the synthesized chimeric E3 ligand-containing molecules induced the UPS-mediated degradation of ERα and AR. The PERM3 peptide was applicable for the development of the ERα and AR degraders using these E3 ligands.

Keywords: Helical peptide; Nuclear receptors; Protein knockdown; Protein–protein interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / metabolism*
  • Humans
  • MCF-7 Cells
  • Nuclear Receptor Coactivator 1
  • Peptides / chemical synthesis
  • Peptides / pharmacology*
  • Proteolysis / drug effects*
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / drug effects


  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Peptides
  • Receptors, Androgen
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1
  • Ubiquitin-Protein Ligases