Development of a Binding Model to Protein Tyrosine Kinases for Substituted Pyrido[2,3-d]pyrimidine Inhibitors

Abstract

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.

Development of anaplastic lymphoma kinase (ALK) small‐molecule inhibitors for cancer therapy

“…Pharmacophore methods for ATP site-directed competitive inhibitors of other kinases may also provide some insights and direction for ALK structure-based drug design and analysis of structure-activity relationships (SAR). [335][336][337] The maturing technology of fragment-based discovery for new lead generation may also be an effective approach for the design of novel ALK inhibitors; for example, fragment-based design of protein kinase inhibitors for other kinase targets has been recently demonstrated, with the discovery of novel chemotypes by virtual screening, NMR and X-ray crystallography approaches. 338,339 While the utility of these types of approaches is clear, it is nonetheless important to note that successful kinase inhibitor development can occur independent of them-as exemplified by Gleevec, which was developed without the benefit of an ABL kinase domain structure.…”

A solid-phase Bcr-Abl kinase assay in 96-well hydrogel plates

“…Pyridopyrimidine compounds are well-characterized and their structureactivity relationships have been studied at length [21,45,46]. These analyses have shown that the substitution of the amino group on the carbon at position 2 (C-2) significantly affects the inhibitory activity.…”

Tyrosine kinase inhibitors: From rational design to clinical trials

“…In the absence of the X-ray structure of a kinase (e.g., EGFR protein tyrosine kinase), pharmacophore models have been constructed and further re®ned with structure-activity relationships (SAR) studies. 2,3,4 These models are now generally applicable and have enabled researchers to exploit structure-based drug design approaches to increase potency and/or selectivity within a lead series.…”