Targeted Inhibition of CBP/p300-NCOA3 Interactions with an α-Methylated Peptide

  • J Med Chem. 2026 Jan 8;69(1):400-412. doi: 10.1021/acs.jmedchem.5c02636.
Aurora Silvestri  1 ,  Judit Osz  1 ,  Alexis Jouin  2 ,  Valentin Bauer  3 ,  Sandra Chalhoub  1 ,  Vladimir Torbeev  2  3 ,  Natacha Rochel  1
Affiliations
  • 1. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258/CNRS UMR7104/, Université de Strasbourg, 67400 Illkirch, France.
  • 2. École Supérieure de Biotechnologie de Strasbourg (ESBS), CNRS UMR 7242 Biotechnology and Cellular Signalling, University of Strasbourg, 67400 Illkirch, France.
  • 3. Institut de Science et d'Ingénierie Supramoléculaires (ISIS), UMR 7006, University of Strasbourg, CNRS, 67000 Strasbourg, France.
PMID: 41401139 DOI: 10.1021/acs.jmedchem.5c02636
Abstract

The CREB-binding protein (CBP) and its paralogue p300 are cellular integrators of various signaling pathways involved in various physiological functions. Together with NCOA proteins, they act as coactivators of nuclear receptors. CBP/p300 and NCOA3 are overexpressed in endocrine cancers, leading to enhanced nuclear receptor activity and promoting tumor progression through activation of oncogenes and regulation of cellular functions. Thus, targeting CBP/p300-NCOA3 has great potential for the development of antitumor agents. As a tool to disrupt disease-related protein-protein interactions, we developed the NCOA3 activation domain 1 (AD1) peptide containing noncanonical α-methylated Amino acids for targeting the intrinsically disordered nuclear coactivator binding domain (NCBD) in CBP/p300. We showed that this peptide variant binds with a stronger affinity to its target proteins than the wild-type peptide and inhibits CBP/p300 acetylase activity. This peptide variant also modulates interactomes and CBP/p300-mediated gene transcription and exhibits effective antiproliferative activity in cell-based assays.

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