title: Development and biological evaluation of a novel aurora A kinase inhibitor.
abstract: STOP DIVIDING: In the quest for antitumorigenic compounds, aurora A kinase has recently emerged as a potential drug target. In this paper three novel aurora inhibitors (shown in the illustration) have been tested for their biological activity in cultured cells. One of them (TC-28) appears to be a promising specific aurora A inhibitor in vivo. The aurora kinase family groups several serine/threonine kinases with key regulatory functions during cell division. The three mammalian members, aurora A, B and C, are frequently over-expressed in human tumors and the aurora A gene is located in a genomic region frequently amplified in breast and colon cancer. All these data have fuelled the idea that aurora kinases are promising targets for anticancer therapy. Indeed some inhibitory compounds are currently being evaluated in clinical trials. However, it was recently shown that mutations in the targeted kinase can confer resistance to a broad range of inhibitors and render patients resistant to treatments. Moreover, aurora A over-expression results in increased resistance to antimitotic agents. The development of new compounds targeting aurora A is therefore highly relevant. We describe here the synthesis of three novel aurora kinase inhibitors, TC-28, TC-34 and TC-107. We report their properties as aurora inhibitors in vitro and their effect on human tissue culture cell lines. Interestingly, our results show that TC-28 has properties compatible with the specific inhibition of aurora A, in vivo.
authors.affiliation: CRG-Cell and Developmental Biology Program, Parc de Recerca Biomedica de Barcelona, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Sardon
authors.forename: Thomas
authors.initials: T
authors.lastname: Cottin
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Athanassios
authors.initials: A
authors.lastname: Giannis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vernos
mesh_terms: D064127:Aurora Kinases; D002453:Cell Cycle / Q000502:physiology; D002923:Cilia / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects
chemical_list: C539622:3-(2-(furan-2-yl)-4-(isopropylamno)quinazolin-6-yl)prop-2-yn-1-ol; C539621:3-(4-(3-fluorophenylamino)quinazolin-6-yl)prop-2-yn-1-ol; C539623:4-(2-(furan-2-yl)-4-(isopropylamino)quinazolin-6-yl)-2-methylbut-3-en-2-ol; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases