N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.
The adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N(2)-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N(2)-NH group and the requirement for an aromatic N(2)-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC(50) = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC(50) = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC(50) = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity.
Hardcastle
Ian R
IR
Northern Institute for Cancer Research, Bedson Building, School of Natural Sciences, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK. I.R.Hardcastle@ncl.ac.uk
Arris
Christine E
CE
Bentley
Johanne
J
Boyle
F Thomas
FT
Chen
Yuzhu
Y
Curtin
Nicola J
NJ
Endicott
Jane A
JA
Gibson
Ashleigh E
AE
Golding
Bernard T
BT
Griffin
Roger J
RJ
Jewsbury
Philip
P
Menyerol
Jerome
J
Mesguiche
Veronique
V
Newell
David R
DR
Noble
Martin E M
ME
Pratt
David J
DJ
Wang
Lan-Zhen
LZ
Whitfield
Hayley J
HJ
D000818:Animals; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013215:Starfish; D013329:Structure-Activity Relationship
D003510:Cyclohexanes; D011687:Purines; D006147:Guanine; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2