Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins

作者：Wei, Jun; Kitada, Shinichi; Rega, Michele F.; Emdadi, Aras; Yuan, Hongbin; Cellitti, Jason; Stebbins, John L.; Zhai, Dayong; Sun, Jiazhi; Yang, Li; Dahl, Russell; Zhang, Ziming; Wu, Bainan; Wang, Si; Reed, Tyler A.; Lawrence, Nicholas; Sebti, Said; Reed, John C.; Pellecchia, Maurizio^*

来源：Molecular Cancer Therapeutics, 2009, 8(4): 904-913.

DOI：10.1158/1535-7163.MCT-08-1050

• SMALL-MOLECULE INHIBITORS
• CELL-DEATH
• APOPTOSIS
• GOSSYPOL
• CANCER
• DISCOVERY
• COMPOUND
• BCL-X(L)
• DESIGN
• MICE

Guided by a combination of nuclear magnetic resonance binding assays and computational docking studies, we synthesized a library of 5,5' substituted Apogossypol derivatives as potent Bcl-X-L antagonists. Each compound was subsequently tested for its ability to inhibit Bcl-XL in an in vitro fluorescence polarization competition assay and exert single-agent proapoptotic activity in human cancer cell lines. The most potent compound BI79D10 binds to Bcl-X-L, Bcl-2, and Mcl-1 with IC50 values of 190, 360, and 520 nmol/L, respectively, and potently inhibits cell growth in the H460 human lung cancer cell line with an EC50 value of 680 nmol/L, expressing high levels of Bcl-2. BI79D10 also effectively induces apoptosis of the RS11846 human lymphoma cell line in a dose-dependent manner and shows little cytotoxicity against bax(-/-)bak(-/-) mouse embryonic fibroblast cells, in which antiapoptotic Bcl-2 family proteins lack a cytoprotective phenotype, implying that BI79D10 has little off-target effects. BI79D10 displays in vivo efficacy in transgenic mice, in which Bcl-2 is overexpressed in splenic B cells. Together with its improved plasma and microsomal stability relative to Apogossypol, BI79D10 represents a lead compound for the development of novel apoptosis-based therapies for cancer. [Mol Cancer Ther 2009;8(4):904-13]

• 出版日期2009-4
• 单位河北医科大学