title: A class of 2,4-bisanilinopyrimidine Aurora A inhibitors with unusually high selectivity against Aurora B.
abstract: The two major Aurora kinases carry out critical functions at distinct mitotic stages. Selective inhibitors of these kinases, as well as pan-Aurora inhibitors, show antitumor efficacy and are now under clinical investigation. However, the ATP-binding sites of Aurora A and Aurora B are virtually identical, and the structural basis for selective inhibition has therefore not been clear. We report here a class of bisanilinopyrimidine Aurora A inhibitors with excellent selectivity for Aurora A over Aurora B, both in enzymatic assays and in cellular phenotypic assays. Crystal structures of two of the inhibitors in complex with Aurora A implicate a single amino acid difference in Aurora B as responsible for poor inhibitory activity against this enzyme. Mutation of this residue in Aurora B (E161T) or Aurora A (T217E) is sufficient to swap the inhibition profile, suggesting that this difference might be exploited more generally to achieve high selectivity for Aurora A.
authors.affiliation: Department of Small Molecule Drug Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aliagas-Martin
authors.forename: Dan
authors.initials: D
authors.lastname: Burdick
authors.forename: Laura
authors.initials: L
authors.lastname: Corson
authors.forename: Jennafer
authors.initials: J
authors.lastname: Dotson
authors.forename: Jason
authors.initials: J
authors.lastname: Drummond
authors.forename: Carter
authors.initials: C
authors.lastname: Fields
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Huang
authors.forename: Thomas
authors.initials: T
authors.lastname: Hunsaker
authors.forename: Tracy
authors.initials: T
authors.lastname: Kleinheinz
authors.forename: Elaine
authors.initials: E
authors.lastname: Krueger
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: John
authors.initials: J
authors.lastname: Moffat
authors.forename: Gail
authors.initials: G
authors.lastname: Phillips
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pulk
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Rawson
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.forename: Leslie
authors.initials: L
authors.lastname: Walker
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Birong
authors.initials: B
authors.lastname: Zhang
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cochran
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases