Controlling Intramolecular Interactions in the Design of Selective, High-Affinity Ligands for the CREBBP Bromodomain

J Med Chem. 2021 Jul 22;64(14):10102-10123. doi: 10.1021/acs.jmedchem.1c00348. Epub 2021 Jul 13.

Abstract

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (<0.1% O2), the inhibition of the CREBBP/EP300 bromodomain results in the enhanced stabilization of HIF-1α.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Benzodiazepinones / chemical synthesis
  • Benzodiazepinones / chemistry
  • Benzodiazepinones / pharmacology*
  • CREB-Binding Protein / antagonists & inhibitors*
  • CREB-Binding Protein / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • E1A-Associated p300 Protein / antagonists & inhibitors*
  • E1A-Associated p300 Protein / metabolism
  • HCT116 Cells
  • Humans
  • Ligands
  • Molecular Structure
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzodiazepinones
  • Ligands
  • Small Molecule Libraries
  • CREB-Binding Protein
  • CREBBP protein, human
  • E1A-Associated p300 Protein
  • EP300 protein, human