title: Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity.
abstract: Cyclin dependent kinases are a key family of kinases involved in cell cycle regulation and are an attractive target for cancer chemotherapy. The roles of four residues of the cyclin-dependent kinase active site in inhibitor selectivity were investigated by producing cyclin-dependent kinase 2 mutants bearing equivalent cyclin-dependent kinase 4 residues, namely F82H, L83V, H84D, and K89T. Assay of the mutants with a cyclin-dependent kinase 4-selective bisanilinopyrimidine shows that the K89T mutation is primarily responsible for the selectivity of this compound. Use of the cyclin-dependent kinase 2-selective 6-cyclohexylmethoxy-2-(4'-sulfamoylanilino)purine (NU6102) shows that K89T has no role in the selectivity, while the remaining three mutations have a cumulative influence. The results indicate that certain residues that are not frequently considered in structure-aided kinase inhibitor design have an important role to play.
authors.affiliation: Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pratt
authors.forename: Jo
authors.initials: J
authors.lastname: Bentley
authors.forename: Philip
authors.initials: P
authors.lastname: Jewsbury
authors.forename: F Tom
authors.initials: FT
authors.lastname: Boyle
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011687:Purines / Q000737:chemistry
chemical_list: C466914:NU6102; D047428:Protein Kinase Inhibitors; D011687:Purines; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4