Structure-based discovery and optimization of potential cancer therapeutics targeting the cell cycle.
Progress has been made recently in the structure-based optimization of novel cell cycle antitumor therapeutics based on cyclin-dependent kinase (CDK) inhibition. A novel inhibitor series based on the 2-amino-4-heteroaryl-pyrimidine scaffold was discovered using the LIDAEUS high-throughput docking methodology, and was subsequently optimized for CDK2 potency through information provided by crystallographic complex structures. A computational study of CDK4 inhibitors led to the incorporation of selectivity determinants into a pyrimidine pharmacophore to generate isoform-specific inhibitors. In addition, molecules from the inhibitor series have been crystallized in complex structures with both monomeric inactive CDK2 and an active complex of CDK2 bound to cyclin A or E. This crystallization revealed that significant differences exist in the affinity of the inhibitors for active and inactive states of CDK2. Information on differences in affinity facilitates the prediction of experimental binding of inhibitors and allows for the further development of structure-guided design.
Thomas
Mark P
MP
Cyclacel Ltd, James Lindsay Place, Dundee Technopole, Dundee, DD1 5JJ, UK.
McInnes
Campbell
C
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000737:chemistry; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases