Identification of Novel Purine and Pyrimidine Cyclin-Dependent Kinase Inhibitors with Distinct Molecular Interactions and Tumor Cell Growth Inhibition Profiles

• Published in: Journal of medicinal chemistry Vol. 43; no. 15; pp. 2797 - 2804
• Main Authors: Arris, Christine E, Boyle, F. Thomas, Calvert, A. Hilary, Curtin, Nicola J, Endicott, Jane A, Garman, Elspeth F, Gibson, Ashleigh E, Golding, Bernard T, Grant, Sharon, Griffin, Roger J, Jewsbury, Philip, Johnson, Louise N, Lawrie, Alison M, Newell, David R, Noble, Martin E. M, Sausville, Edward A, Schultz, Robert, Yu, Wyatt
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 27-07-2000
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; CDC2 Protein Kinase - antagonists & inhibitors; CDC2 Protein Kinase - chemistry; CDC2-CDC28 Kinases; Crystallography, X-Ray; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - chemistry; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Humans; Hydrogen Bonding; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - chemistry; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured; Antineoplastic agent; Human; Nitroso compound; Cyclohexane derivatives; Enzyme; Nitrogen heterocycle; Transferases; Enzyme inhibitor; Cytotoxicity; Inhibitor enzyme complex; X ray diffraction; In vitro; Modeling; Cell line; Structure activity relation; Protein kinase; Six membered ring; Molecular model; Bicyclic compound; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990628o

Substituted guanines and pyrimidines were tested as inhibitors of cyclin B1/CDK1 and cyclin A3/CDK2 and soaked into crystals of monomeric CDK2. O 6-Cyclohexylmethylguanine (NU2058) was a competitive inhibitor of CDK1 and CDK2 with respect to ATP (K i values:  CDK1, 5 ± 1 μM; CDK2, 12 ± 3 μM) and formed a triplet of hydrogen bonds (i.e., NH-9 to Glu 81, N-3 to Leu 83, and 2-NH2 to Leu 83). The triplet of hydrogen bonding and CDK inhibition was reproduced by 2,6-diamino-4-cyclohexylmethyloxy-5-nitrosopyrimidine (NU6027, K i values:  CDK1, 2.5 ± 0.4 μM; CDK2, 1.3 ± 0.2 μM). Against human tumor cells, NU2058 and NU6027 were growth inhibitory in vitro (mean GI50 values of 13 ± 7 μM and 10 ± 6 μM, respectively), with a pattern of sensitivity distinct from flavopiridol and olomoucine. These CDK inhibition and chemosensitivity data indicate that the distinct mode of binding of NU2058 and NU6027 has direct consequences for enzyme and cell growth inhibition.