Structure-guided design of pyrazolo[1,5-a]pyrimidines as inhibitors of human cyclin-dependent kinase 2.
The protein structure guided design of a series of pyrazolo[1,5-a]pyrimidines with high potency for human cyclin-dependent kinase 2 (CDK2) is described. Some examples were shown to inhibit the growth of human colon tumour cells, were equipotent for CDK1 and were selective against GSK-3beta and other kinases.
Williamson
Douglas S
DS
Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB1 6GB, United Kingdom. d.williamson@vernalis.com
Parratt
Martin J
MJ
Bower
Justin F
JF
Moore
Jonathan D
JD
Richardson
Christine M
CM
Dokurno
Pawel
P
Cansfield
Andrew D
AD
Francis
Geraint L
GL
Hebdon
Richard J
RJ
Howes
Rob
R
Jackson
Philip S
PS
Lockie
Andrea M
AM
Murray
James B
JB
Nunns
Claire L
CL
Powles
Jenifer
J
Robertson
Alan
A
Surgenor
Allan E
AE
Torrance
Christopher J
CJ
D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011743:Pyrimidines; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2