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Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles

Lookup NU author(s): Dr Christine Arris, Professor Alan Calvert, Professor Nicola Curtin, Professor Jane Endicott, Professor Bernard Golding, Professor Roger Griffin, Professor Herbie Newell, Professor Martin Noble

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Abstract

Substituted guanines and pyrimidines were tested as inhibitors of cyclin B1/CDK1 and cyclin A3/CDK2 and soaked into crystals of monomeric CDK2. O6-Cyclohexylmethylguanine (NU2058) was a competitive inhibitor of CDK1 and CDK2 with respect to ATP (Ki 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, Ki 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.


Publication metadata

Author(s): Arris CE, Boyle FT, Calvert AH, Curtin NJ, Endicott JA, Garman EF, Gibson AE, Golding BT, Grant S, Griffin RJ, Jewsbury P, Johnson LN, Lawrie AM, Newell DR, Noble MEM, Sausville EA, Schultz R, Yu W

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2000

Volume: 43

Issue: 15

Pages: 2797-2804

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm990628o

DOI: 10.1021/jm990628o

PubMed id: 10956187


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