Novel small-molecule inhibitors of Bcl-XL to treat lung cancer.

Abstract

Bcl-XL is a major antiapoptotic protein in the Bcl-2 family whose overexpression is more widely observed in human lung cancer cells than that of Bcl-2, suggesting that Bcl-XL is more biologically relevant and therefore a better therapeutic target for lung cancer. Here, we screened small molecules that selectively target the BH3 domain (aa 90-98) binding pocket of Bcl-XL using the UCSF DOCK 6.1 program suite and the NCI chemical library database. We identified two new Bcl-XL inhibitors (BXI-61 and BXI-72) that exhibit selective toxicity against lung cancer cells compared with normal human bronchial epithelial cells. Fluorescence polarization assay reveals that BXI-61 and BXI-72 preferentially bind to Bcl-XL protein but not Bcl2, Bcl-w, Bfl-1/A1, or Mcl-1 in vitro with high binding affinities. Treatment of cells with BXI-72 results in disruption of Bcl-XL/Bak or Bcl-XL/Bax interaction, oligomerization of Bak, and cytochrome c release from mitochondria. Importantly, BXI-61 and BXI-72 exhibit more potent efficacy against human lung cancer than ABT-737 but less degree in platelet reduction in vivo. BXI-72 overcomes acquired radioresistance of lung cancer. On the basis of our findings, the development of BXI(s) as a new class of anticancer agents is warranted and represents a novel strategy for improving lung cancer outcome.

• Authors: Dongkyoo Park, Andrew T Magis, Rui Li, Taofeek K Owonikoko, Gabriel L Sica, Shi-Yong Sun, Suresh S Ramalingam, Fadlo R Khuri, Walter J Curran, Xingming Deng
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 17 Pg. 5485-96 (Sep 01 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23824742 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-737
• Acridines
• Aminopyridines
• BAK1 protein, human
• BXI-61
• BXI-72
• Benzimidazoles
• Biphenyl Compounds
• Nitrophenols
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• Small Molecule Libraries
• Sulfonamides
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-X Protein
• Cytochromes c

Topics

• Acridines (pharmacology)
• Aminopyridines (pharmacology)
• Animals
• Apoptosis (drug effects, radiation effects)
• Benzimidazoles (pharmacology)
• Biphenyl Compounds (pharmacology)
• Blotting, Western
• Cell Proliferation (drug effects, radiation effects)
• Cytochromes c (metabolism)
• Female
• Humans
• Lung (cytology, drug effects)
• Lung Neoplasms (drug therapy, mortality, pathology)
• Mice
• Mice, Nude
• Nitrophenols (pharmacology)
• Piperazines (pharmacology)
• Protein Multimerization
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)
• Radiation Tolerance (drug effects)
• Radiation, Ionizing
• Small Molecule Libraries
• Sulfonamides (pharmacology)
• Survival Rate
• bcl-2 Homologous Antagonist-Killer Protein (antagonists & inhibitors, metabolism)
• bcl-X Protein (antagonists & inhibitors, metabolism)