Pioneering 4,11-Dioxo-4,11-dihydro-1 H-anthra[2,3- d]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 (K_D = 163 nM) of AQIM-I to ILF3/NF110 was detected by surface plasmon resonance.