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Biological evaluation of 4,5,7-trisubstituted Indeno[1,2-b]indoles reveals a potent inhibitor of protein kinase CK2 in tumor cells with diverse anti-cancer effects and preferential cytoplasmic localization
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International audience. The highly pleiotropic and constitutively active serine/threonine protein kinase CK2 is considered a keytarget in cancer. The indeno[1,2-b]indole scaffold was previously shown to provide derivatives exhibitingstrong CK2 inhibition and satisfactory drug-like characteristics. In this work, we evaluated one 4,5,7-trisubstituted indeno[1,2-b]indole derivative for its intracellular inhibition of CK2 activity and theaccompanying effects on proliferation, migration and apoptosis in cancer cells. The compound 5-isopropyl-4-methoxy-7-methyl-5,6,7,8-tetrahydro-indeno[1,2-b]indole-9,10-dione (5a-2) strongly inhibited CK2activity in vitro with IC50 value of 25 nM and in cultured A431, A549 and LNCaP cell lines (> 75% inhibitionat 20 µM). The intracellular inhibition of CK2 by 5a-2 was comparable to that induced by the reference CK2inhibitor CX-4945, though the latter exhibited > 6-fold higher inhibitory potency toward CK2 in vitro (IC50 =3.7 nM). A possible explanation for this discrepancy is the significantly higher intracellular concentrationsof 5a-2 compared to CX-4945 following their cellular uptake. Compared to CX-4945, 5a-2 induced similaranti-proliferative, weaker pro-apoptotic but stronger anti-migratory effects on cancer cells. Thesevariations can be partly attributed to the observed differences in the subcellular localization of bothcompounds whereby 71% of the uptaken 5a-2 molecules were found in the cytoplasm while 49% ofintracellular CX-4945 was detectable in the nuclear fraction.Our study emphasizes the potential of indeno[1,2-b]indole as an interesting framework for developingpotent CK2 inhibitors and highlights the significance of subcellular distribution in dictating preferentialcellular effects of CK2 inhibitors.
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