Cyclin-dependent kinase 4 inhibitors as a treatment for cancer. Part 1: identification and optimisation of substituted 4,6-bis anilino pyrimidines.
Using a high-throughput screening campaign, we identified the 4,6-bis anilino pyrimidines as inhibitors of the cyclin-dependent kinase, CDK4. Herein we describe the further chemical modification and use of X-ray crystallography to develop potent and selective in vitro inhibitors of CDK4.
Beattie
John F
JF
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Breault
Gloria A
GA
Ellston
Rebecca P A
RP
Green
Stephen
S
Jewsbury
Philip J
PJ
Midgley
Catherine J
CJ
Naven
Russell T
RT
Minshull
Claire A
CA
Pauptit
Richard A
RA
Tucker
Julie A
JA
Pease
J Elizabeth
JE
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases