Perturbing pro-survival proteins using quinoxaline derivatives: a structure-activity relationship study.

Abstract

In HeLa cells the combinatorial knockdown of Bcl-xL and Mcl-1 is sufficient to induce spontaneous apoptosis. Quinoxaline derivatives were screened for the induction of Mcl-1 dependent apoptosis using a cell line without functional Bcl-xL. Quinoxaline urea analog 1 h was able to specifically induce apoptosis in an Mcl-1 dependent manner. We demonstrate that even small changes to 1h results in dramatic loss of activity. In addition, 1 h and ABT-737 synergistically inhibit cell growth and induce apoptosis. Our results also suggest that 1h could have therapeutic potential against ABT-737 refractory cancer.

• Authors: Rajkumar Rajule, Vashti C Bryant, Hernando Lopez, Xu Luo, Amarnath Natarajan
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 7 Pg. 2227-34 (Apr 01 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22386982 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• ABT-737
• Biphenyl Compounds
• Myeloid Cell Leukemia Sequence 1 Protein
• Nitrophenols
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• Quinoxalines
• Sulfonamides
• bcl-X Protein

Topics

• Apoptosis (drug effects)
• Biphenyl Compounds (pharmacology)
• HeLa Cells
• Humans
• Myeloid Cell Leukemia Sequence 1 Protein
• Nitrophenols (pharmacology)
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• Quinoxalines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Sulfonamides (pharmacology)
• bcl-X Protein (antagonists & inhibitors, genetics, metabolism)