title: SAR and inhibitor complex structure determination of a novel class of potent and specific Aurora kinase inhibitors.
abstract: A novel series of 5-aminopyrimidinyl quinazolines has been developed from anilino-quinazoline 1, which was identified in a high throughput screen for Aurora A. Introduction of the pyrimidine ring and optimisation of the substituents both on this ring and at the C7 position of the quinazoline led to the discovery of compounds that are highly specific Aurora kinase inhibitors. Co-crystallisation of one of these inhibitors with a fragment of Aurora A shows the importance of the benzamido group in achieving selectivity.
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG,UK. Nicola.Heron@astrazeneca.com
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Heron
authors.forename: Malcolm
authors.initials: M
authors.lastname: Anderson
authors.forename: David P
authors.initials: DP
authors.lastname: Blowers
authors.forename: Jason
authors.initials: J
authors.lastname: Breed
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Eden
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
authors.forename: George B
authors.initials: GB
authors.lastname: Hill
authors.forename: Trevor
authors.initials: T
authors.lastname: Johnson
authors.forename: Frederic H
authors.initials: FH
authors.lastname: Jung
authors.forename: Helen H J
authors.initials: HH
authors.lastname: McMiken
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Mortlock
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Pannifer
authors.forename: Richard A
authors.initials: RA
authors.lastname: Pauptit
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pink
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Roberts
authors.forename: Siân
authors.initials: S
authors.lastname: Rowsell
mesh_terms: D064127:Aurora Kinases; D001550:Benzamidines / Q000737:chemistry; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001550:Benzamidines; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C032157:benzamidine