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

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 (KD = 163 nM) of AQIM-I to ILF3/NF110 was detected by surface plasmon resonance.生存素（Survivin）是癌症治疗领域极具吸引力的新型靶点，但由于其不具备酶促活性，被归类为不可成药靶点。本文详述了我们通过靶向ILF3/NF110，开发一系列作为生存素抑制剂的新型4,11-二氧代-4,11-二氢-1H-蒽并[2,3-d]咪唑-3-鎓衍生物的研究工作。通过系统性结构修饰，我们筛选得到先导化合物AQIM-I：该化合物对非小细胞肺癌A549细胞的半数抑制浓度（IC₅₀）仅为9 nM，且相较于人正常细胞，对实体瘤细胞增殖的抑制活性具有超过700倍的选择性。后续生物学研究表明，AQIM-I可显著抑制生存素的表达与细胞集落形成，并诱导活性氧（Reactive Oxygen Species, ROS）生成、细胞凋亡、细胞周期阻滞、DNA损伤以及细胞自噬。此外，启动子-荧光素酶报告基因实验结果显示，AQIM-I可浓度依赖性地减弱ILF3/NF110过表达所增强的生存素启动子活性；同时通过表面等离子体共振（Surface Plasmon Resonance, SPR）技术检测到，AQIM-I与ILF3/NF110之间存在特异性结合，其解离常数（K_D）为163 nM。