title: 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.affiliation: Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Rajule
authors.forename: Vashti C
authors.initials: VC
authors.lastname: Bryant
authors.forename: Hernando
authors.initials: H
authors.lastname: Lopez
authors.forename: Xu
authors.initials: X
authors.lastname: Luo
authors.forename: Amarnath
authors.initials: A
authors.lastname: Natarajan
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011810:Quinoxalines; D013449:Sulfonamides; D051020:bcl-X Protein