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

• Published in: Bioorganic & medicinal chemistry Vol. 28; no. 15; pp. 115595 - 115599
• Main Authors: Yokoo, Hidetomo, Ohoka, Nobumichi, Naito, Mikihiko, Demizu, Yosuke
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2020; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Helical peptide; Life Sciences & Biomedicine; Nuclear receptors; Pharmacology & Pharmacy; Physical Sciences; Protein knockdown; Protein–protein interaction; Science & Technology; Protein knockdown; Helical peptide; Nuclear receptors; Protein–protein interaction; Protein-protein interaction; PROTEIN-DEGRADATION; UBIQUITIN LIGASE; HELICAL PEPTIDES; INHIBITORS
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2020.115595

[Display omitted] 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.