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PDBsum entry 1e1x
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Protein kinase
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PDB id
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1e1x
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Identification of novel purine and pyrimidine cyclin-Dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles.
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Authors
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C.E.Arris,
F.T.Boyle,
A.H.Calvert,
N.J.Curtin,
J.A.Endicott,
E.F.Garman,
A.E.Gibson,
B.T.Golding,
S.Grant,
R.J.Griffin,
P.Jewsbury,
L.N.Johnson,
A.M.Lawrie,
D.R.Newell,
M.E.Noble,
E.A.Sausville,
R.Schultz,
W.Yu.
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Ref.
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J Med Chem, 2000,
43,
2797-2804.
[DOI no: ]
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PubMed id
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Abstract
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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 microM; CDK2, 12 +/- 3 microM) 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 microM; CDK2, 1.3 +/- 0.2 microM). Against human tumor
cells, NU2058 and NU6027 were growth inhibitory in vitro (mean GI50 values of 13
+/- 7 microM and 10 +/- 6 microM, 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.
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