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O6-substituted guanines and 4-substituted pyrimidines: a novel class of antiproliferative 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 CurtinORCiD, Emeritus Professor Bernard Golding, Professor Roger Griffin, Professor Herbie Newell

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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 (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.

Publication metadata

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

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

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