title: Apogossypol derivatives as pan-active inhibitors of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins.
abstract: Guided by nuclear magnetic resonance (NMR) binding assays and computational docking studies, a series of 5,5' substituted apogossypol derivatives was synthesized that resulted in potent pan-active inhibitors of antiapoptotic Bcl-2 family proteins. Compound 8r inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, Mcl-1, and Bfl-1 with IC(50) values of 0.76, 0.32, 0.28, and 0.73 microM, respectively. The compound also potently inhibits cell growth of human lung cancer and BP3 human B-cell lymphoma cell lines with EC(50) values of 0.33 and 0.66 microM, respectively. Compound 8r shows little cytotoxicity against bax(-/-)bak(-/-) cells, indicating that it kills cancers cells via the intended mechanism. The compound also displays in vivo efficacy in transgenic mice in which Bcl-2 is overexpressed in splenic B-cells. Together with its improved chemical, plasma, and microsomal stability relative to compound 2 (apogossypol), compound 8r represents a promising drug lead for the development of novel apoptosis-based therapies for cancer.
authors: Burnham Institute for Medical Research, La Jolla, California 92037, USA.
authors: Jun
authors: J
authors: Wei
authors: Shinichi
authors: S
authors: Kitada
authors: Michele F
authors: MF
authors: Rega
authors: John L
authors: JL
authors: Stebbins
authors: Dayong
authors: D
authors: Zhai
authors: Jason
authors: J
authors: Cellitti
authors: Hongbin
authors: H
authors: Yuan
authors: Aras
authors: A
authors: Emdadi
authors: Russell
authors: R
authors: Dahl
authors: Ziming
authors: Z
authors: Zhang
authors: Li
authors: L
authors: Yang
authors: John C
authors: JC
authors: Reed
authors: Maurizio
authors: M
authors: Pellecchia
mesh_terms: D000478:Alkylation; D000577:Amides / Q000737:chemistry; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006072:Gossypol / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000577:Amides; D007659:Ketones; D019253:Proto-Oncogene Proteins c-bcl-2; C492806:apogossypol; D006072:Gossypol