Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL

Nat Cell Biol. 2001 Feb;3(2):173-82. doi: 10.1038/35055085.


To study the role of the BH3 domain in mediating pro-apoptotic and anti-apoptotic activities of Bcl-2 family members, we identified a series of novel small molecules (BH3Is) that inhibit the binding of the Bak BH3 peptide to Bcl-xL. NMR analyses revealed that BH3Is target the BH3-binding pocket of Bcl-xL. Inhibitors specifically block the BH3-domain-mediated heterodimerization between Bcl-2 family members in vitro and in vivo and induce apoptosis. Our results indicate that BH3-dependent heterodimerization is the key function of anti-apoptotic Bcl-2 family members and is required for the maintenance of cellular homeostasis.

Publication types

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

MeSH terms

  • Apoptosis / physiology*
  • BH3 Interacting Domain Death Agonist Protein
  • Blotting, Western
  • Carrier Proteins / metabolism
  • Caspases / metabolism
  • Cell Line
  • Cell Separation
  • Cytochrome c Group / metabolism
  • Dimerization
  • Flow Cytometry
  • Fluorescence Polarization / methods
  • Genes, Reporter
  • Humans
  • In Situ Nick-End Labeling
  • Magnetic Resonance Spectroscopy
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-X Protein


  • BAK1 protein, human
  • BCL2L1 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Carrier Proteins
  • Cytochrome c Group
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-X Protein
  • Caspases