Development of a binding model to protein tyrosine kinases for substituted pyrido[2,3-d]pyrimidine inhibitors.
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.
Trumpp-Kallmeyer
S
S
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
Rubin
J R
JR
Humblet
C
C
Hamby
J M
JM
Showalter
H D
HD
D000595:Amino Acid Sequence; D000818:Animals; D016367:Baculoviridae; D000081247:CSK Tyrosine-Protein Kinase; D002645:Chickens; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007313:Insecta / Q000166:cytology / Q000201:enzymology / Q000821:virology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000378:metabolism; D013329:Structure-Activity Relationship; D019061:src-Family Kinases
D011480:Protease Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D000242:Cyclic AMP; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D017868:Cyclic AMP-Dependent Protein Kinases