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A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes

Jagat C Borah1, Shiraz Mujtaba, Ioannis Karakikes

  • 1Department of Structural and Chemical Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.

Chemistry & Biology
|April 26, 2011
PubMed

Insights

A novel small molecule, ischemin, inhibits the interaction between tumor suppressor p53 and CREB-binding protein (CBP). This targeted inhibition prevents apoptosis in ischemic cardiomyocytes, offering a new therapeutic strategy for myocardial ischemia.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cardiovascular Research

Background:

  • Tumor suppressor p53 is a key regulator of cellular stress responses.
  • Excessive p53 activity exacerbates injury and death in myocardial ischemia.
  • p53 activation relies on acetylation by CREB-binding protein (CBP) and CBP recruitment for gene expression.

Purpose of the Study:

  • To develop a small molecule inhibitor targeting CBP's bromodomain.
  • To investigate the effects of this inhibitor on p53 activity and cardiomyocyte apoptosis.

Main Methods:

  • Structure-guided design of the small molecule ischemin.
  • Analysis of post-translational modifications on p53 and histones.
  • Assessment of p53-CBP interaction and transcriptional activity in cells.
  • Evaluation of apoptosis in ischemic cardiomyocytes.

Main Results:

  • Ischemin inhibits the acetyl-lysine binding activity of CBP's bromodomain.
  • Ischemin alters p53 and histone post-translational modifications.
  • Ischemin reduces p53-CBP interaction and transcriptional activity.
  • Ischemin prevents apoptosis in ischemic cardiomyocytes.

Conclusions:

  • Small molecule inhibition of CBP bromodomain is a viable therapeutic strategy.
  • Modulating acetylation-mediated interactions offers a novel approach for treating myocardial ischemia.
  • Ischemin demonstrates potential for protecting cardiomyocytes during ischemic events.

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