使用喹喔啉衍生物扰乱抗生存蛋白：一项构效关系研究。
Perturbing pro-survival proteins using quinoxaline derivatives: a structure-activity relationship study.
机构信息
Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, United States.
出版信息
Bioorg Med Chem. 2012 Apr 1;20(7):2227-34. doi: 10.1016/j.bmc.2012.02.022. Epub 2012 Feb 16.
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.
摘要
在 HeLa 细胞中，Bcl-xL 和 Mcl-1 的组合敲低足以诱导自发凋亡。使用没有功能性 Bcl-xL 的细胞系筛选了喹喔啉衍生物诱导 Mcl-1 依赖性凋亡。喹喔啉脲类似物 1h 能够以 Mcl-1 依赖的方式特异性诱导凋亡。我们证明，即使 1h 发生微小变化，也会导致活性急剧丧失。此外，1h 和 ABT-737 协同抑制细胞生长并诱导凋亡。我们的结果还表明，1h 可能对 ABT-737 耐药的癌症具有治疗潜力。
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