title: Structure-guided discovery of cyclin-dependent kinase inhibitors.
abstract: 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.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
authors.forename: Thierry O
authors.initials: TO
authors.lastname: Fischmann
authors.forename: Alan
authors.initials: A
authors.lastname: Hruza
authors.forename: José S
authors.initials: JS
authors.lastname: Duca
authors.forename: Lata
authors.initials: L
authors.lastname: Ramanathan
authors.forename: Todd
authors.initials: T
authors.lastname: Mayhood
authors.forename: William T
authors.initials: WT
authors.lastname: Windsor
authors.forename: Hung V
authors.initials: HV
authors.lastname: Le
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Guzi
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dwyer
authors.forename: Kamil
authors.initials: K
authors.lastname: Paruch
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Doll
authors.forename: Emma
authors.initials: E
authors.lastname: Lees
authors.forename: David
authors.initials: D
authors.lastname: Parry
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Seghezzi
authors.forename: Vincent
authors.initials: V
authors.lastname: Madison
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases