Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X(L)

Chem Biol. 2004 Mar;11(3):389-95. doi: 10.1016/j.chembiol.2004.02.020.


Antiapoptotic Bcl-2-family proteins Bcl-2 and Bcl-X(L) have been recently validated as drug discovery targets for cancer. Here, by using a combination of molecular modeling, NMR-based structural analysis, fluorescence polarization assays, and cell-based assays, we have designed and characterized a novel proapoptotic compound targeting these proteins. Our compound, Apogossypol, is capable of binding and inhibiting Bcl-2 and Bcl-X(L) with high affinity and induces apoptosis of tumor cell lines. Mechanistic studies on the action of our compound were also performed via confocal microscopy that provided real-time detection of the interaction with Bcl-X(L) in intact cells. Finally, preliminary data on cells freshly isolated from patients affected by chronic lymphocytic leukemia strongly suggest potential applications of Bcl-2 antagonists as chemosensitizers in cancer therapy.

Publication types

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

MeSH terms

  • Acetates / chemistry
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Design*
  • Gossypol / analogs & derivatives*
  • Gossypol / chemical synthesis
  • Gossypol / chemistry*
  • Gossypol / isolation & purification
  • Gossypol / pharmacology*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Microscopy, Confocal
  • Models, Molecular
  • Molecular Structure
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Spectrometry, Fluorescence
  • Structure-Activity Relationship
  • Time Factors
  • bcl-X Protein


  • Acetates
  • BCL2L1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • apogossypol
  • bcl-X Protein
  • Gossypol