title: Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors.
abstract: N-(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1) was found active (IC50=808 nM) in a high throughput screening (HTS) for CDK2 inhibitors. By exploiting crystal structures of several complexes between CDK2 and inhibitors and applying structure-based drug design (SBDD), we rapidly discovered a very potent and selective CDK2 inhibitor 4-[(5-isopropyl-1,3-thiazol-2-yl)amino] benzenesulfonamide (compound 4, IC50=20 nM). The syntheses, structure-based analog design, kinases inhibition data and X-ray crystallographic structures of CDK2/inhibitor complexes are reported.
authors.affiliation: Department of Chemistry, Nerviano Medical Sciences, Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy. anna.vulpetti@nervianoms.com
authors.forename: Anna
authors.initials: A
authors.lastname: Vulpetti
authors.forename: Elena
authors.initials: E
authors.lastname: Casale
authors.forename: Fulvia
authors.initials: F
authors.lastname: Roletto
authors.forename: Raffaella
authors.initials: R
authors.lastname: Amici
authors.forename: Manuela
authors.initials: M
authors.lastname: Villa
authors.forename: Paolo
authors.initials: P
authors.lastname: Pevarello
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015195:Drug Design; D019277:Entropy; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D051357:Cyclin-Dependent Kinase 2