title: Hydrosoluble benzo[e]pyridoindolones as potent inhibitors of aurora kinases.
abstract: Aurora kinases play an essential role in mitotic progression and are potentially druggable targets in cancer therapy. We identified benzo[e]pyridoindoles (BePI) as powerful aurora kinase inhibitors. Their efficiency was demonstrated both in enzymatic inhibition studies and in cell culture assays. New BePI molecules were synthesized, and a structure-activity relationship study was conducted with the aim of improving the activity and solubility of the lead compound. Tetracyclic BePI derivatives are characterized by a particular curved shape, and the presence of an oxo group on the pyridine ring was found to be required for aurora kinase B inhibition. New hydrosoluble benzo[e]pyridoindolones were subsequently designed, and their efficacy was tested by a combination of cell-cycle analysis and time-lapse experiments in live cells. The most active BePI derivative, 13 b, inhibited the cell cycle, drove cells to polyploidy, and eventually induced apoptosis. It exhibited high antiproliferative activity in HeLa cells with an IC(50) value of 63 nM. Relative to compounds tested in clinical trials, this antiproliferative potency places 13 b among the top 10 aurora kinase inhibitors. Our results justify further in vivo evaluation in preclinical animal models of cancer.
authors.affiliation: Biology Laboratory, CRI-INSERM/UJF U823, Institut Albert Bonniot, Université Joseph Fourier, 38706 La Tronche, France.
authors.forename: Ly-Thuy-Tram
authors.initials: LT
authors.lastname: Le
authors.forename: Hong-Lien
authors.initials: HL
authors.lastname: Vu
authors.forename: Delphine
authors.initials: D
authors.lastname: Naud-Martin
authors.forename: Marianne
authors.initials: M
authors.lastname: Bombled
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Nguyen
authors.forename: Annie
authors.initials: A
authors.lastname: Molla
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; C082732:3-methoxy-7H-8-methyl-11-((3'-amino)propylamino)benzo(e)pyrido(4,3-b)indole; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases