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PDBsum entry 1ke9
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Contents |
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* Residue conservation analysis
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PDB id:
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Transferase
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Title:
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Cyclin-dependent kinase 2 (cdk2) complexed with 3-{[4-({[amino(imino) methyl]aminosulfonyl)anilino]methylene}-2-oxo-2,3-dihydro-1h-indole
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Structure:
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Cell division protein kinase 2. Chain: a. Synonym: cdk2, p33 protein kinase. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
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Resolution:
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2.00Å
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R-factor:
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0.203
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R-free:
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0.238
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Authors:
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H.N.Bramson,J.Corona,S.T.Davis,S.H.Dickerson,M.Edelstein,S.V.Frye, R.T.Gampe,A.M.Hassell,L.M.Shewchuk,L.F.Kuyper
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Key ref:
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H.N.Bramson
et al.
(2001).
Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis.
J Med Chem,
44,
4339-4358.
PubMed id:
DOI:
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Date:
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14-Nov-01
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Release date:
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14-May-02
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PROCHECK
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Headers
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References
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P24941
(CDK2_HUMAN) -
Cyclin-dependent kinase 2 from Homo sapiens
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Seq:
Struc:
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298 a.a.
281 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.11.22
- cyclin-dependent kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
44:4339-4358
(2001)
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PubMed id:
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Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis.
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H.N.Bramson,
J.Corona,
S.T.Davis,
S.H.Dickerson,
M.Edelstein,
S.V.Frye,
R.T.Gampe,
P.A.Harris,
A.Hassell,
W.D.Holmes,
R.N.Hunter,
K.E.Lackey,
B.Lovejoy,
M.J.Luzzio,
V.Montana,
W.J.Rocque,
D.Rusnak,
L.Shewchuk,
J.M.Veal,
D.H.Walker,
L.F.Kuyper.
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ABSTRACT
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Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dione
3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were
shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initial lead
compound was prepared as a homologue of the
3-benzylidene-1,3-dihydro-2H-indol-2-one class of kinase inhibitor.
Crystallographic analysis of the lead compound bound to CDK2 provided the basis
for analogue design. A semiautomated method of ligand docking was used to select
compounds for synthesis, and a number of compounds with low nanomolar inhibitory
activity versus CDK2 were identified. Enzyme binding determinants for several
analogues were evaluated by X-ray crystallography. Compounds in this series
inhibited CDK2 with a potency approximately 10-fold greater than that for CDK1.
Members of this class of inhibitor cause an arrest of the cell cycle and have
shown potential utility in the prevention of chemotherapy-induced alopecia.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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C.R.Reddy,
E.Jithender,
G.Krishna,
G.V.Reddy,
and
B.Jagadeesh
(2011).
A novel acid-catalyzed C5-alkylation of oxindoles using alcohols.
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Org Biomol Chem,
9,
3940-3947.
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B.V.Silva,
N.M.Ribeiro,
M.D.Vargas,
M.Lanznaster,
J.W.Carneiro,
R.Krogh,
A.D.Andricopulo,
L.C.Dias,
and
A.C.Pinto
(2010).
Synthesis, electrochemical studies and anticancer activity of ferrocenyl oxindoles.
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Dalton Trans,
39,
7338-7344.
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K.Engels,
C.Beyer,
M.L.Suárez Fernández,
F.Bender,
M.Gassel,
G.Unden,
R.J.Marhöfer,
J.C.Mottram,
and
P.M.Selzer
(2010).
Inhibition of Eimeria tenella CDK-related kinase 2: From target identification to lead compounds.
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ChemMedChem,
5,
1259-1271.
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A.Bakan,
J.S.Lazo,
P.Wipf,
K.M.Brummond,
and
I.Bahar
(2008).
Toward a molecular understanding of the interaction of dual specificity phosphatases with substrates: insights from structure-based modeling and high throughput screening.
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Curr Med Chem,
15,
2536-2544.
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H.R.Lawrence,
R.Pireddu,
L.Chen,
Y.Luo,
S.S.Sung,
A.M.Szymanski,
M.L.Yip,
W.C.Guida,
S.M.Sebti,
J.Wu,
and
N.J.Lawrence
(2008).
Inhibitors of Src homology-2 domain containing protein tyrosine phosphatase-2 (Shp2) based on oxindole scaffolds.
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J Med Chem,
51,
4948-4956.
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M.P.Mazanetz,
and
P.M.Fischer
(2007).
Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases.
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Nat Rev Drug Discov,
6,
464-479.
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M.Sassatelli,
F.Bouchikhi,
B.Aboab,
F.Anizon,
D.Fabbro,
M.Prudhomme,
and
P.Moreau
(2007).
In-vitro antiproliferative activities and kinase inhibitory potencies of glycosyl-isoindigo derivatives.
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Anticancer Drugs,
18,
1069-1074.
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A.D.Pyle,
L.F.Lock,
and
P.J.Donovan
(2006).
Neurotrophins mediate human embryonic stem cell survival.
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Nat Biotechnol,
24,
344-350.
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C.Kung,
D.M.Kenski,
K.Krukenberg,
H.D.Madhani,
and
K.M.Shokat
(2006).
Selective kinase inhibition by exploiting differential pathway sensitivity.
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Chem Biol,
13,
399-407.
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G.A.Landrum,
J.E.Penzotti,
and
S.Putta
(2006).
Feature-map vectors: a new class of informative descriptors for computational drug discovery.
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J Comput Aided Mol Des,
20,
751-762.
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J.Sridhar,
N.Akula,
and
N.Pattabiraman
(2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
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AAPS J,
8,
E204-E221.
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C.Kung,
D.M.Kenski,
S.H.Dickerson,
R.W.Howson,
L.F.Kuyper,
H.D.Madhani,
and
K.M.Shokat
(2005).
Chemical genomic profiling to identify intracellular targets of a multiplex kinase inhibitor.
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Proc Natl Acad Sci U S A,
102,
3587-3592.
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H.Dureja,
and
A.K.Madan
(2005).
Topochemical models for prediction of cyclin-dependent kinase 2 inhibitory activity of indole-2-ones.
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J Mol Model,
11,
525-531.
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N.C.Waters,
and
J.A.Geyer
(2003).
Cyclin-dependent protein kinases as therapeutic drug targets for antimalarial drug development.
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Expert Opin Ther Targets,
7,
7.
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E.A.Sausville
(2002).
Complexities in the development of cyclin-dependent kinase inhibitor drugs.
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Trends Mol Med,
8,
S32-S37.
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M.Knockaert,
P.Greengard,
and
L.Meijer
(2002).
Pharmacological inhibitors of cyclin-dependent kinases.
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Trends Pharmacol Sci,
23,
417-425.
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P.L.Toogood
(2002).
Progress toward the development of agents to modulate the cell cycle.
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Curr Opin Chem Biol,
6,
472-478.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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Links
