Broad-Spectrum Anticancer Activity and Pharmacokinetic Properties of a Prenyloxy-Substituted Indeno[1,2-<i>b</i>]indole Derivative, Discovered as CK2 Inhibitor

• Main Authors: Ehab El-Awaad (Author), Robin Birus (Author), Christelle Marminon (Author), Zouhair Bouaziz (Author), Laurens Ballentin (Author), Dagmar Aichele (Author), Marc Le Borgne (Author), Joachim Jose (Author)
• Format: Book
• Published: MDPI AG, 2021-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

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 (IC₅₀ = 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.

Item Description

10.3390/ph14060542
1424-8247