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

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 anti-apoptotic 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 μM, 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 μM, respectively. Compound 8r shows little cytotoxicity against bax(−/−)bak(−/−) cells, indicating that it kills cancers cells via the intented 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