SAR and inhibitor complex structure determination of a novel class of potent and specific Aurora kinase inhibitors.
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.
Heron
Nicola M
NM
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG,UK. Nicola.Heron@astrazeneca.com
Anderson
Malcolm
M
Blowers
David P
DP
Breed
Jason
J
Eden
Jonathan M
JM
Green
Stephen
S
Hill
George B
GB
Johnson
Trevor
T
Jung
Frederic H
FH
McMiken
Helen H J
HH
Mortlock
Andrew A
AA
Pannifer
Andrew D
AD
Pauptit
Richard A
RA
Pink
Jennifer
J
Roberts
Nicola J
NJ
Rowsell
Siân
S
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
D001550:Benzamidines; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C032157:benzamidine