| Summary: | Protein kinase CK2 is involved in regulating cellular processes, such as cell cycle, proliferation, migration, and apoptosis, making it an attractive anticancer target. We previously described a prenyloxy-substituted indeno[1,2-<i>b</i>]indole (5-isopropyl-4-(3-methylbut-2-enyloxy)-5,6,7,8-tetrahydroindeno[1,2-<i>b</i>]indole-9,10-dione (<b>4p</b>)) as a very potent inhibitor of CK2 holoenzyme (IC<sub>50</sub> = 25 nM). Here, we report the broad-spectrum anticancer activity of <b>4p</b> and provide substantial progress on its pharmacokinetic properties. Using a cell-based CK2 activity assay and live-cell imaging of cultured A431, A549, and LNCaP cancer cell lines, cellular CK2 target engagement was shown as well as strong antiproliferative, anti-migratory and apoptosis-inducing effects of <b>4p</b>. Furthermore, evidence was found for the ability of <b>4p</b> to disrupt A549 spheroid cohesion. A series of LC-MS/MS experiments revealed high and rapid cellular uptake (intracellular concentration is approximately 5 µM after 1 h incubation) and low metabolic stability of <b>4p</b>. These results point to the value of <b>4p</b> as a potent CK2 inhibitor with promising anticancer activities and should trigger future medicinal chemistry efforts to improve the drug-like properties of this compound.
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