Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases.
The identification of 8-ethyl-2-phenylamino-8H-pyrido[2, 3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2, 3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC(50) = 0.004 microM ([ATP] = 25 microM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb(+) cells in the G(1)-phase of the cell division cycle.
Barvian
M
M
Departments of Chemistry and Cancer Research, Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
Boschelli
D H
DH
Cossrow
J
J
Dobrusin
E
E
Fattaey
A
A
Fritsch
A
A
Fry
D
D
Harvey
P
P
Keller
P
P
Garrett
M
M
La
F
F
Leopold
W
W
McNamara
D
D
Quin
M
M
Trumpp-Kallmeyer
S
S
Toogood
P
P
Wu
Z
Z
Zhang
E
E
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007313:Insecta / Q000166:cytology; D007700:Kinetics; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases