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

Abstract

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.

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@article{Becattini2004RationalDA, title={Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X(L).}, author={Barbara Becattini and Shinichi Kitada and Marilisa Leone and Edward Z Monosov and Sharon Chandler and Dayong Zhai and Thomas J. Kipps and John C. Reed and Maurizio Pellecchia}, journal={Chemistry & biology}, year={2004}, volume={11 3}, pages={389-95} }