New Potent and Selective Inhibitor of Pim-1/3 Protein Kinases Sensitizes Human Colon Carcinoma Cells to Doxorubicin

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)

Volume 16, 12 Issues, 2016

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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex

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New Potent and Selective Inhibitor of Pim-1/3 Protein Kinases Sensitizes Human Colon Carcinoma Cells to Doxorubicin

Anti-Cancer Agents in Medicinal Chemistry, 14(9): 1228-1236.

Author(s): Pascale Moreau, Lyubov G. Dezhenkova, Fabrice Anizon, Lionel Nauton, Vincent Thery, Shuguang Liang, Dmitry N. Kaluzhny and Alexander A Shtil.

Affiliation: Clermont Universite, Universite Blaise Pascal, Institut de Chimie de Clermont Ferrand (ICCF) - UMR CNRS 6296, 24 Avenue des Landais, BP 10448 63000 Clermont- Ferrand, France.


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.


Anticancer therapy, colon carcinoma, Pim kinases, serine/threonine protein kinases, small molecular weight inhibitors.

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Article Details

Volume: 14
Issue Number: 9
First Page: 1228
Last Page: 1236
Page Count: 9
DOI: 10.2174/1871520614666140825124456
Price: $58

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