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

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• 作者：Rajkumar Rajule^a ; ^&dagger ; ; Vashti C. Bryant^a ; ^&dagger ; ; Hernando Lopez^a ; ^&dagger ; ; Xu Luo^a ; Amarnath Natarajan^a ; ^b ; ^{anatarajan@unmc.edu}
• 关键词：Mcl-1 ; myeloid cell leukemia 1 ; Bcl-xL ; B-cell lymphoma extra large ; Bcl-2 ; B-cell lymphoma 2 ; BH ; Bcl-2 homology ; XIAP ; X-linked inhibitor of apoptosis protein ; PARP ; poly (ADP-ribose) polymerase ; Dox ; doxycycline ; GFP ; green fluorescent protein
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 April, 2012
• 卷：20
• 期：7
• 页码：2227-2234
• 文件大小：982 K

摘要

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 1h 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, 1h 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.