Pioneering 4,11-Dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium Compounds as Promising Survivin Inhibitors by Targeting ILF3/NF110 for Cancer Therapy

1区 · 医学

Article

作者: Zhang, Zhenfeng ; Gao, Feng ; Luo, Yanli ; Xia, Xuelin ; Yan, Deyue ; Dong, Yachun ; Yuan, Jing ; Zhang, Wanbin ; Liu, Zhanxiong ; Wang, Penghui

Survivin is a novel attractive target for cancer therapy; however, it is considered undruggable because it lacks enzymatic activities. Herein, we describe our efforts toward the discovery of a novel series of 4,11-dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium derivatives as survivin inhibitors by targeting ILF3/NF110. Intensive structural modifications led us to identify a lead compound AQIM-I, which remarkably inhibited nonsmall cell lung cancer cells A549 with an IC₅₀ value of 9 nM and solid tumor cell proliferation with more than 700-fold selectivity against human normal cells. Further biological studies revealed that compound AQIM-I significantly inhibited survivin expression and colony formation and induced ROS production, apoptosis, cell cycle arrest, DNA damage, and autophagy. Furthermore, the promoter-luciferase reporter assay showed that AQIM-I attenuated the survivin promoter activity enhanced by the overexpression of ILF3/NF110 in a concentration-dependent manner, and specific binding (K_D = 163 nM) of AQIM-I to ILF3/NF110 was detected by surface plasmon resonance.

Journal of Medicinal Chemistry

Pioneering 4,11-Dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium Compounds as Promising Survivin Inhibitors by Targeting ILF3/NF110 for Cancer Therapy

作者: Luo, Yanli ; Zhang, Zhenfeng ; Gao, Feng ; Zhang, Wanbin ; Liu, Zhanxiong ; Yan, Deyue ; Dong, Yachun ; Yuan, Jing ; Wang, Penghui ; Xia, Xuelin

Survivin is a novel attractive target for cancer therapy, however, it is considered undruggable because it lacks enzymic activities.Herein, we describe our efforts toward the discovery of a novel series of 4,11-dioxo-4,11-dihydro-1H-anthra[2,3-d]imidazol-3-ium derivatives as survivin inhibitors by targeting ILF3/NF110.Intensive structural modifications led us to identify a lead compound AQIM-I, which remarkably inhibited nonsmall cell lung cancer cell A549 with an IC50 value of 9 nM and solid tumor cell proliferation with more than 700-fold selectivity against human normal cells.Further biol. studies revealed that compound AQIM-I significantly inhibited survivin expression and colony formation, and induced ROS production, apoptosis, cell cycle arrest, DNA damage, and autophagy.Furthermore, promoter-luciferase reporter assay showed that AQIM-I attenuated the survivin promoter activity enhanced by overexpression of ILF3/NF110 in a concentration-dependent manner, and specific binding (KD = 163 nM) of AQIM-I to ILF3/NF110 were detected by SPR.

100 项与 AQIM-I 相关的药物交易

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