Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: protein structure-guided design and SAR.
Crystallographic and modelling data, in conjunction with a medicinal chemistry template-hopping approach, led to the identification of a series of novel and potent inhibitors of human cyclin-dependent kinase 2 (CDK2), with selectivity over glycogen synthase kinase-3beta (GSK-3beta). One example had a CDK2 IC(50) of 120 nM and showed selectivity over GSK-3beta of 167-fold.
Richardson
Christine M
CM
Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB1 6GB, UK.
Williamson
Douglas S
DS
Parratt
Martin J
MJ
Borgognoni
Jenifer
J
Cansfield
Andrew D
AD
Dokurno
Pawel
P
Francis
Geraint L
GL
Howes
Rob
R
Moore
Jonathan D
JD
Murray
James B
JB
Robertson
Alan
A
Surgenor
Allan E
AE
Torrance
Christopher J
CJ
D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D051357:Cyclin-Dependent Kinase 2