Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins.

Abstract

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-XL 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-XL, 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.

• Authors: Jun Wei, Shinichi Kitada, Michele F Rega, Aras Emdadi, Hongbin Yuan, Jason Cellitti, John L Stebbins, Dayong Zhai, Jiazhi Sun, Li Yang, Russell Dahl, Ziming Zhang, Bainan Wu, Si Wang, Tyler A Reed, Hong-Gang Wang, Nicholas Lawrence, Said Sebti, John C Reed, Maurizio Pellecchia
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 4 Pg. 904-13 (Apr 2009) ISSN: 1535-7163 [Print] United States
• PMID: 19372563 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bak1 protein, mouse
• Bax protein (53-86)
• Bax protein, mouse
• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• Bcl2l11 protein, rat
• Mcl1 protein, mouse
• Membrane Proteins
• Membranes, Artificial
• Myeloid Cell Leukemia Sequence 1 Protein
• Peptide Fragments
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• apogossypol
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• bcl-X Protein
• Gossypol

Topics

• Animals
• Apoptosis Regulatory Proteins (metabolism)
• Bcl-2-Like Protein 11
• Cell Survival (drug effects)
• Female
• Fluorescence Polarization
• Gossypol (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Lymphoma (drug therapy, metabolism, pathology)
• Magnetic Resonance Spectroscopy
• Male
• Membrane Proteins (metabolism)
• Membranes, Artificial
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Mice, Transgenic
• Microsomes, Liver
• Models, Molecular
• Myeloid Cell Leukemia Sequence 1 Protein
• Peptide Fragments (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• Rats
• Tumor Cells, Cultured
• bcl-2 Homologous Antagonist-Killer Protein (physiology)
• bcl-2-Associated X Protein (physiology)
• bcl-X Protein (metabolism)