title: Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach.
abstract: Aurora A and Aurora B are potential targets for anticancer drug development due to their roles in tumorigenesis and disease progression. To identify small-molecule inhibitors of the Aurora kinases, we undertook a structure-based design approach that used three-dimensional structural models of the Aurora A kinase and molecular docking simulations of chemical entities. Based on these computational methods, a new generation of inhibitors derived from quinazoline and pyrimidine-based tricyclic scaffolds were synthesized and evaluated for Aurora A kinase inhibitory activity, which led to the identification of 4-(6,7-dimethoxy-9H-1,3,9-triaza-fluoren-4-yl)-piperazine-1-carbothioic acid [4-(pyrimidin-2-ylsulfamoyl)-phenyl]-amide. The lead compound showed selectivity for the Aurora kinases when it was evaluated against a panel of diverse kinases. Additionally, the compound was evaluated in cell-based assays, showing a dose-dependent decrease in phospho-histone H3 levels and an arrest of the cell cycle in the G(2)-M fraction. Although biological effects were observed only at relatively high concentrations, this chemical series provides an excellent starting point for drug optimization and further development.
authors.affiliation: College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Warner
authors.forename: Sridevi
authors.initials: S
authors.lastname: Bashyam
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Vankayalapati
authors.forename: David J
authors.initials: DJ
authors.lastname: Bearss
authors.forename: Haiyong
authors.initials: H
authors.lastname: Han
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Hurley
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006657:Histones / Q000378:metabolism; D006801:Humans; D007854:Lead / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013871:Thiones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C513934:4-(6,7-dimethoxy-9H-1,3,9-triazafluoren-4-yl)piperazine-1-carbothioic acid (4-(pyrimidin-2-ylsulfamoyl)phenyl)amide; D000970:Antineoplastic Agents; D006657:Histones; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013871:Thiones; D007854:Lead; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases