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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.

Apogossypol Derivatives as Pan-Active Inhibitors of Antiapoptotic B-Cell Lymphoma/Leukemia-2 (Bcl-2) Family Proteins