New Potent and Selective Inhibitor of Pim-1/3 Protein Kinases Sensitizes Human Colon Carcinoma Cells to Doxorubicin
Lyubov G. Dezhenkova,
Dmitry N. Kaluzhny,
Alexander A. Shtil.
The Pim protein kinases (provirus insertion site of Moloney murine leukemia virus) have been identified as important actors
involved in tumor cell survival, proliferation, migration and invasion. Therefore, inhibition of Pim activity by low molecular weight
compounds is under investigation as a part of anticancer therapeutic strategies. We have synthesized a series of pyrrolo[2,3-a]carbazole
derivatives that significantly inhibited Pim protein kinases at submicromolar concentrations. Particularly, benzodiazocine derivative 1
potently inhibited Pim-1 and -3 isoforms in in vitro kinase assays (IC50 8 nM and 13 nM, respectively), whereas Pim-2 activity was less
affected (IC50 350 nM). We show here that no inhibitory effect of 1 was detectable at 1 µM against other 22 serine/threonine and tyrosine
kinases. In addition, 1, possessing a planar pyrrolocarbazole scaffold, demonstrated no significant binding to DNA, nor was it a potent
topoisomerase I inhibitor, suggesting that 1 is likely to be highly selective for Pim-1 and -3. Importantly, whereas 1 exerted a negligible
cytotoxicity for human colon carcinoma HCT116 cell line at concentrations >10 µM within 72 h of cell exposure, it synergized at nontoxic
concentrations with the antitumor drug doxorubicin (Dox) in killing HCT116 cells: IC50 of Dox alone and Dox+1 were ~200 nM
and ~25 nM, respectively. These data strongly suggest that 1 emerges as a prospective antitumor drug candidate due to its selectivity to
individual Pim protein kinases and the ability to potentiate the efficacy of conventional chemotherapeutics.
Keywords: Anticancer therapy, colon carcinoma, Pim kinases, serine/threonine protein kinases, small molecular weight inhibitors.
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