Linked Life Data

9599227

Source:http://linkedlifedata.com/resource/pubmed/id/9599227

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
1998-6-15
pubmed:abstractText
Previously, our laboratories have reported on a new class of highly potent tyrosine kinase inhibitors based on the pyrido[2, 3-d]pyrimidine core template. To understand the structural basis for the potency and specificity, a model for the binding mode of this class of inhibitors to the tyrosine kinase domains of c-Src, PDGFr, FGFr, and EGFr tyrosine kinases was developed from structural information (principally utilizing the catalytic domain of c-AMP-dependent protein kinase as template) and structure-activity relationship (SAR) information. In the resulting docking mode, the pyrido[2,3-d]pyrimidine template shows a hydrogen-bonding pattern identical to that of olomoucine. The 6-aryl substituent of the heterocycle is located deep in the binding cleft in a pocket not used by ATP, which helps to confer high-affinity binding as well as specificity. The 2-anilino and 2-(dialkylamino)alkylamino substituents as well as the 7-urea substituent of inhibitors within this class are located at the entrance of the binding cleft and make contact with residues in the hinge region between the two kinase lobes. This allows considerable variability and bulk tolerance for C-2 and N-7 substituents. The models presented here are consistent with the SAR seen for the inhibition of a number of isolated enzymes and provide a structural basis to explain their specificity. They have been used successfully to design new highly potent protein kinase inhibitors.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
21
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1752-63
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed-meshheading:9599227-Amino Acid Sequence, pubmed-meshheading:9599227-Animals, pubmed-meshheading:9599227-Baculoviridae, pubmed-meshheading:9599227-Chickens, pubmed-meshheading:9599227-Crystallography, X-Ray, pubmed-meshheading:9599227-Cyclic AMP, pubmed-meshheading:9599227-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:9599227-Humans, pubmed-meshheading:9599227-Hydrogen Bonding, pubmed-meshheading:9599227-Insects, pubmed-meshheading:9599227-Mice, pubmed-meshheading:9599227-Models, Molecular, pubmed-meshheading:9599227-Molecular Sequence Data, pubmed-meshheading:9599227-Protease Inhibitors, pubmed-meshheading:9599227-Protein Binding, pubmed-meshheading:9599227-Protein Conformation, pubmed-meshheading:9599227-Protein-Tyrosine Kinases, pubmed-meshheading:9599227-Pyridines, pubmed-meshheading:9599227-Pyrimidines, pubmed-meshheading:9599227-Receptor, Epidermal Growth Factor, pubmed-meshheading:9599227-Receptors, Fibroblast Growth Factor, pubmed-meshheading:9599227-Receptors, Platelet-Derived Growth Factor, pubmed-meshheading:9599227-Structure-Activity Relationship
pubmed:year
1998
pubmed:articleTitle
Development of a binding model to protein tyrosine kinases for substituted pyrido[2,3-d]pyrimidine inhibitors.
pubmed:affiliation
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
pubmed:publicationType
Journal Article, In Vitro