Structure-Based design of 2-Arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-Dependent kinases 1 and 2
| Autor: | Philip J. Jewsbury, Jane A. Endicott, Veronique Mesguiche, Nicola J. Curtin, J Bentley, Rachel Parsons, David R. Newell, Yuzhu Cheng, Lan Z. Wang, Martin E.M. Noble, Ian R. Hardcastle, Kerry L. Sayle, A. Hilary Calvert, D.J. Pratt, Roger J. Griffin, F. Thomas Boyle, Bernard T. Golding |
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| Rok vydání: | 2003 |
| Předmět: |
Stereochemistry
medicine.drug_class Clinical Biochemistry Cyclin A Pharmaceutical Science Antineoplastic Agents Carboxamide Biochemistry Chemical synthesis Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound Cyclin-dependent kinase CDC2 Protein Kinase Drug Discovery CDC2-CDC28 Kinases medicine Humans Transferase Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Molecular Structure biology Cyclin-Dependent Kinase 2 Organic Chemistry Nitroso Sulfonamide Pyrimidines chemistry Enzyme inhibitor Drug Design biology.protein Molecular Medicine Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 13:3079-3082 |
| ISSN: | 0960-894X |
| Popis: | A series of O 4 -cyclohexylmethyl-5-nitroso-6-aminopyrimidines bearing 2-arylamino substituents was synthesised and evaluated for CDK1 and CDK2 inhibitory activity. Consistent with analogous studies with O 6 -cyclohexylmethylpurines, 2-arylaminopyrimidines with a sulfonamide or carboxamide group at the 4′-position were potent inhibitors, with IC 50 values against CDK2 of 1.1±0.3 and 34±8 nM, respectively. The crystal structure of the 4′-carboxamide derivative, in complex with phospho-Thr160 CDK2/cyclin A, confirmed the expected binding mode of the inhibitor, and revealed an additional interaction between the carboxamide function and an aspartate residue. |
| Databáze: | OpenAIRE |
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