title: Structural basis for the inhibition of Aurora A kinase by a novel class of high affinity disubstituted pyrimidine inhibitors.
abstract: The 2.25 A crystal structure of a complex of Aurora A kinase (AIKA) with cyclopropanecarboxylic acid-(3-(4-(3-trifluoromethyl-phenylamino)-pyrimidin-2-ylamino)-phenyl)-amide 1 is described here. The inhibitor binding mode is novel, with the cyclopropanecarboxylic acid moiety directed towards the solvent exposed region of the ATP-binding pocket, and several induced structural changes in the active-site compared with other published AIK structures. This structure provides context for the available SAR data on this compound class, and could be exploited for the design of analogs with increased affinity and selectivity for AIK.
authors.affiliation: ActiveSight, 4045 Sorrento Valley Blvd., San Diego, CA 92121, USA.
authors.forename: Leslie W
authors.initials: LW
authors.lastname: Tari
authors.forename: Isaac D
authors.initials: ID
authors.lastname: Hoffman
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bensen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hunter
authors.forename: Jay
authors.initials: J
authors.lastname: Nix
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Nelson
authors.forename: Duncan E
authors.initials: DE
authors.lastname: McRee
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Swanson
mesh_terms: D000818:Animals; D064127:Aurora Kinases; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D066246:ErbB Receptors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases