Target structure-based discovery of small molecules that block human p53 and CREB binding protein association

Chem Biol. 2006 Jan;13(1):81-90. doi: 10.1016/j.chembiol.2005.10.014.

Abstract

Lysine acetylation of human tumor suppressor p53 in response to cellular stress signals is required for its function as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report small molecules that block lysine 382-acetylated p53 association with the bromodomain of the coactivator CBP, an interaction essential for p53-induced transcription of the cell cycle inhibitor p21 in response to DNA damage. These chemicals were discovered in target structure-guided nuclear magnetic resonance spectroscopy screening of a focused chemical library constructed based on the structural knowledge of CBP bromodomain/p53-AcK382 binding. Structural characterization shows that these chemicals inhibit CBP/p53 association by binding to the acetyl-lysine binding site of the bromodomain. Cell-based functional assays demonstrate that the lead chemicals can modulate p53 stability and function in response to DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • CREB-Binding Protein / antagonists & inhibitors*
  • CREB-Binding Protein / chemistry*
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism
  • DNA Damage
  • Drug Design*
  • Drug Evaluation, Preclinical*
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Weight
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Spectrometry, Fluorescence
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Ligands
  • Tumor Suppressor Protein p53
  • CREB-Binding Protein