title: Benzo[e]pyridoindoles, novel inhibitors of the aurora kinases.
abstract: Aurora kinases are serine/threonine protein kinases that are involved in cancer development and are important targets for cancer therapy. By high throughput screening of a chemical library we found that benzo[e]pyridoindole derivatives inhibited Aurora kinase. The most potent compound (compound 1) was found to be an ATP competitive inhibitor, which inhibited in vitro Aurora kinases at the nanomolar range. It prevented, ex vivo, the phosphorylation of Histone H3, induced mitosis exit without chromosome segregation, known phenomena observed upon Aurora B inactivation. This compound was also shown to affect the localization of Aurora B, since in the presence of the inhibitor the enzyme was delocalized on the whole chromosomes and remained associated with the chromatin of newly formed nuclei. In addition, compound 1 inhibited the growth of different cell lines derived from different carcinoma. Its IC(50) for H358 NSCLC (Non Small Cancer Lung Cells), the most sensitive cell line, was 145 nM. Furthermore compound 1 was found to be efficient towards multicellular tumor spheroid growth. It exhibited minimal toxicity in mice while it had some potency towards aggressive NSCLC tumors. Benzo[e]pyridoindoles represent thus a potential new lead for the development of Aurora kinase inhibitors.
authors.affiliation: INSERM: U823 Institut Albert Bonniot, Université Joseph Fourier, La Tronche, France.
authors.forename: Thi My-Nhung
authors.initials: TM
authors.lastname: Hoang
authors.forename: Bertrand
authors.initials: B
authors.lastname: Favier
authors.forename: Annie
authors.initials: A
authors.lastname: Valette
authors.forename: Caroline
authors.initials: C
authors.lastname: Barette
authors.forename: Chi Hung
authors.initials: CH
authors.lastname: Nguyen
authors.forename: Laurence
authors.initials: L
authors.lastname: Lafanechère
authors.forename: David S
authors.initials: DS
authors.lastname: Grierson
authors.forename: Stéfan
authors.initials: S
authors.lastname: Dimitrov
authors.forename: Annie
authors.initials: A
authors.lastname: Molla
mesh_terms: D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D020090:Chromosome Segregation; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries
chemical_list: D002843:Chromatin; D006657:Histones; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D054852:Small Molecule Libraries; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases