title: Structure-based design and protein X-ray analysis of a protein kinase inhibitor.
abstract: A 5-aryl-1H-pyrazole molecular scaffold was designed to ligate the ATP binding site of cyclin dependent kinase 2 (CDK2) on the basis of crystallographic information. A search of the compound collection of Novartis using this scaffold as substructure query led to the identification of PKF049-365 as a representative of a new class of inhibitors of the cell cycle kinases CDK1/2. The three-dimensional structure of CDK2 in complex with PKF049-365 was subsequently determined by protein crystallography and refined to 1.53 A resolution. The X-ray analysis confirmed the binding mode expected from the design hypothesis. In addition, it revealed an alternative binding orientation involving a second tautomeric form of the inhibitor that was not envisaged during the design stage.
authors.affiliation: Novartis Pharmaceuticals Inc., Oncology Research, CH-4002 Basel, Switzerland. pascal.furet@pharma.novartis.com
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.forename: André
authors.initials: A
authors.lastname: Strauss
authors.forename: Sylvie
authors.initials: S
authors.lastname: Raccuglia
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rondeau
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors; D014961:X-Ray Diffraction
chemical_list: D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors