title: 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.
authors.affiliation: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Becattini
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kitada
authors.forename: Marilisa
authors.initials: M
authors.lastname: Leone
authors.forename: Edward
authors.initials: E
authors.lastname: Monosov
authors.forename: Sharon
authors.initials: S
authors.lastname: Chandler
authors.forename: Dayong
authors.initials: D
authors.lastname: Zhai
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000085:Acetates / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006072:Gossypol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D008958:Models, Molecular; D015394:Molecular Structure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013997:Time Factors; D051020:bcl-X Protein
chemical_list: D000085:Acetates; C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C492806:apogossypol; D051020:bcl-X Protein; D006072:Gossypol