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

作者：Wei, Jun; Kitada, Shinichi; Rega, Michele F.; Stebbins, John L.; Zhai, Dayong; Cellitti, Jason; Yuan, Hongbin; Emdadi, Aras; Dahl, Russell; Zhang, Ziming; Yang, Li; Reed, John C.; Pellecchia, Maurizio^*

来源：Journal of Medicinal Chemistry, 2009, 52(14): 4511-4523.

DOI：10.1021/jm900472s

• SMALL-MOLECULE INHIBITORS
• STRUCTURE-BASED DISCOVERY
• STRUCTURE-BASED DESIGN
• LUNG-CANCER
• X-L
• BCL-X(L) ANTAGONISTS
• INDUCED APOPTOSIS
• UP-REGULATION
• MITOCHONDRIA
• GOSSYPOL

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 IC50 values of 0.76, 0.32, 0.28, and 0.73 mu M, respectively. The compound also potently inhibits cell growth of human lung cancer and BP3 human B-cell lymphoma cell lines with EC50 values of 0.33 and 0.66 mu M, 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.

• 出版日期2009-7-23
• 单位河北医科大学