title: New potent and selective inhibitor of Pim-1/3 protein kinases sensitizes human colon carcinoma cells to doxorubicin.
abstract: 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.
authors.forename: Pascale
authors.initials: P
authors.lastname: Moreau
authors.forename: Lyubov G
authors.initials: LG
authors.lastname: Dezhenkova
authors.forename: Fabrice
authors.initials: F
authors.lastname: Anizon
authors.forename: Lionel
authors.initials: L
authors.lastname: Nauton
authors.forename: Vincent
authors.initials: V
authors.lastname: Thery
authors.forename: Shuguang
authors.initials: S
authors.lastname: Liang
authors.forename: Dmitry N
authors.initials: DN
authors.lastname: Kaluzhny
authors.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. Pascale.MOREAU@univ-bpclermont.fr.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; C490587:PIM2 protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D059003:Topoisomerase Inhibitors; D004317:Doxorubicin; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim