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PDBsum entry 2b54
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References listed in PDB file
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Key reference
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Title
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Synthesis and biological evaluation of 1-Aryl-4,5-Dihydro-1h-Pyrazolo[3,4-D]pyrimidin-4-One inhibitors of cyclin-Dependent kinases.
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Authors
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J.A.Markwalder,
M.R.Arnone,
P.A.Benfield,
M.Boisclair,
C.R.Burton,
C.H.Chang,
S.S.Cox,
P.M.Czerniak,
C.L.Dean,
D.Doleniak,
R.Grafstrom,
B.A.Harrison,
R.F.Kaltenbach,
D.A.Nugiel,
K.A.Rossi,
S.R.Sherk,
L.M.Sisk,
P.Stouten,
G.L.Trainor,
P.Worland,
S.P.Seitz.
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Ref.
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J Med Chem, 2004,
47,
5894-5911.
[DOI no: ]
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PubMed id
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Abstract
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Using a high-throughput screening strategy, a series of
1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-ones was identified that
inhibit the cyclin-dependent kinase (CDK) 4/cyclin D1 complex-mediated
phosphorylation of a protein substrate with IC(50)s in the low micromolar range.
On the basis of preliminary structure-activity relationships (SAR), a model was
proposed in which these inhibitors occupy the ATP-binding site of the enzyme,
forming critical hydrogen bonds to the same residue (Val96) to which the amino
group in ATP is presumed to bind. X-ray diffraction studies on a later
derivative bound to CDK2 support this binding mode. Iterative cycles of
synthesis and screening lead to a novel series of potent, CDK2-selective
6-(arylmethyl)pyrazolopyrimidinones. Placement of a hydrogen-bond donor in the
meta-position on the 6-arylmethyl group resulted in approximately 100-fold
increases in CDK4 affinity, giving ligands that were equipotent inhibitors of
CDK4 and CDK2. These compounds exhibit antiproliferative effects in the NCI
HCT116 and other cell lines. The potency of these antiproliferative effects is
enhanced in anilide derivatives and translates into tumor growth inhibition in a
mouse xenograft model.
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