1. Design and synthesis of peptide-based chimeric molecules to induce degradation of the estrogen and androgen receptors
- Author
-
Mikihiko Naito, Hidetomo Yokoo, Yosuke Demizu, and Nobumichi Ohoka
- Subjects
Ubiquitin-Protein Ligases ,Clinical Biochemistry ,Pharmaceutical Science ,Estrogen receptor ,Peptide ,01 natural sciences ,Biochemistry ,Protein–protein interaction ,Nuclear Receptor Coactivator 1 ,Ubiquitin ,Drug Discovery ,Coactivator ,Humans ,Molecular Biology ,chemistry.chemical_classification ,biology ,010405 organic chemistry ,Chemistry ,Cereblon ,Organic Chemistry ,Estrogen Receptor alpha ,Ubiquitination ,0104 chemical sciences ,Cell biology ,Androgen receptor ,010404 medicinal & biomolecular chemistry ,Nuclear receptor ,Receptors, Androgen ,Drug Design ,Proteolysis ,biology.protein ,MCF-7 Cells ,Molecular Medicine ,Peptides - Abstract
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.
- Published
- 2020