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PDBsum entry 3dog
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Transferase, cell cycle
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PDB id
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3dog
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Contents |
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298 a.a.
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262 a.a.
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268 a.a.
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References listed in PDB file
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Key reference
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Title
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N-&Amp;-N, A new class of cell death-Inducing kinase inhibitors derived from the purine roscovitine.
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Authors
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K.Bettayeb,
H.Sallam,
Y.Ferandin,
F.Popowycz,
G.Fournet,
M.Hassan,
A.Echalier,
P.Bernard,
J.Endicott,
B.Joseph,
L.Meijer.
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Ref.
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Mol Cancer Ther, 2008,
7,
2713-2724.
[DOI no: ]
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PubMed id
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Abstract
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Cyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities
in tumors. Ten low molecular weight pharmacologic inhibitors of CDKs are
currently in clinical trials against various cancers, including the
2,6,9-trisubstituted purine (R)-roscovitine (CYC202/Seliciclib). We here report
the characterization of N-&-N1, a bioisoster of roscovitine displaying
improved antitumoral properties. N-&-N1 shows exquisite selectivity for
CDKs, with 2- to 3-fold enhanced potency compared with (R)-roscovitine.
Inhibition of retinoblastoma protein phosphorylation and RNA polymerase II Ser2
phosphorylation in neuroblastoma SH-SY5Y cells exposed to N-&-N1 indicates
that N-&-N1 is able to inhibit CDKs in a cellular context. N-&-N1 also
down-regulates the expression of RNA polymerase. Cocrystal structures of
N-&-N1 and (R)-roscovitine in complex with CDK2/cyclin A reveal that both
inhibitors adopt similar binding modes. A competitive assay shows that, compared
with (R)-roscovitine, N-&-N1 has reduced affinity for Erk2 and pyridoxal
kinase. N-&-N1 triggers cell death in a panel of diverse cell lines. Cell
death is accompanied by events characteristic of apoptosis: cytochrome c
release, activation of effector caspases, and poly(ADP-ribose) polymerase
cleavage. Induction of p53 and p21CIP1 and down-regulation of the Mcl-1
antiapoptotic factor were also observed. Studies in mice show that N-&-N1
has pharmacokinetics properties similar to those of (R)-roscovitine. Altogether,
these results show that analogues of (R)-roscovitine can be designed with
improved antitumor potential.
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