ABSTRACT
An imidazole series of cyclin-dependent kinase (CDK) inhibitors has been developed. Protein inhibitor structure determination has provided an understanding of the emerging structure activity trends for the imidazole series. The introduction of a methyl sulfone at the aniline terminus led to a more orally bioavailable CDK inhibitor that was progressed into clinical development.
Subject(s)
Cyclin-Dependent Kinases/antagonists & inhibitors , Imidazoles/chemistry , Aniline Compounds/chemistry , Animals , Cell Cycle Proteins/chemistry , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Mice , Models, Chemical , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Human thymidine phosphorylase (HTP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), is overexpressed in certain solid tumors where it is linked to poor prognosis. HTP expression is utilized for certain chemotherapeutic strategies and is also thought to play a role in tumor angiogenesis. We determined the structure of HTP bound to the small molecule inhibitor 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride (TPI). The inhibitor appears to mimic the substrate transition state, which may help explain the potency of this inhibitor and the catalytic mechanism of pyrimidine nucleotide phosphorylases (PYNPs). Further, we have confirmed the validity of the HTP structure as a template for structure-based drug design by predicting binding affinities for TPI and other known HTP inhibitors using in silico docking techniques. This work provides the first structural insight into the binding mode of any inhibitor to this important drug target and forms the basis for designing novel inhibitors for use in anticancer therapy.
Subject(s)
Models, Molecular , Protein Binding , Protein Folding , Pyrrolidines/chemistry , Thymidine Phosphorylase/metabolism , Uracil/analogs & derivatives , Uracil/chemistry , Crystallization , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Protein Structure, Tertiary , Pyrrolidines/pharmacology , Uracil/pharmacologyABSTRACT
A novel series of 5-aminopyrimidinyl quinazolines has been developed from anilino-quinazoline 1, which was identified in a high throughput screen for Aurora A. Introduction of the pyrimidine ring and optimisation of the substituents both on this ring and at the C7 position of the quinazoline led to the discovery of compounds that are highly specific Aurora kinase inhibitors. Co-crystallisation of one of these inhibitors with a fragment of Aurora A shows the importance of the benzamido group in achieving selectivity.