Structure-guided discovery of cyclin-dependent kinase inhibitors.
CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding mode featuring two hydrogen bonds (H-bonds) to the backbone of the kinase hinge region. Even though ab initio computations indicated that the imidazopyrazine core would bind more tightly to the hinge, pyrazolopyrimidines gain an advantage in potency through participation of N4 in an H-bond network involving two catalytic residues and bridging water molecules. Further insight into inhibitor/CDK2 interactions was gained from analysis of additional crystal structures. Significant gains in potency were obtained by optimizing the fit of hydrophobic substituents to the gatekeeper region of the ATP binding site. The most potent inhibitors have good selectivity.
Fischmann
Thierry O
TO
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Hruza
Alan
A
Duca
José S
JS
Ramanathan
Lata
L
Mayhood
Todd
T
Windsor
William T
WT
Le
Hung V
HV
Guzi
Timothy J
TJ
Dwyer
Michael P
MP
Paruch
Kamil
K
Doll
Ronald J
RJ
Lees
Emma
E
Parry
David
D
Seghezzi
Wolfgang
W
Madison
Vincent
V
D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases