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PDBsum entry 1vyz
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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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Structure of cdk2 complexed with pnu-181227
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Structure:
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Cell division protein kinase 2. Chain: a. Synonym: 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: high five.
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Resolution:
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2.21Å
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R-factor:
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0.238
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R-free:
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0.280
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Authors:
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P.Pevarello,M.G.Brasca,R.Amici,P.Orsini,G.Traquandi,L.Corti,C.Piutti, P.Sansonna,M.Villa,B.S.Pierce,M.Pulici,G.Giordano,K.Martina, E.Lfritzen,R.A.Nugent,E.Casale,A.Cameron,M.Ciomei,F.Roletto, A.Isacchi,G.Fogliatto,E.Pesenti,W.Pastori,W.Marsiglio,K.L.Leach, P.M.Clare,F.Fiorentini,M.Varasi,A.Vulpetti,M.A.Warpehoski
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Key ref:
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P.Pevarello
et al.
(2004).
3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.
J Med Chem,
47,
3367-3380.
PubMed id:
DOI:
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Date:
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07-May-04
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Release date:
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17-Jun-04
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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.
279 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
47:3367-3380
(2004)
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PubMed id:
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3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.
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P.Pevarello,
M.G.Brasca,
R.Amici,
P.Orsini,
G.Traquandi,
L.Corti,
C.Piutti,
P.Sansonna,
M.Villa,
B.S.Pierce,
M.Pulici,
P.Giordano,
K.Martina,
E.L.Fritzen,
R.A.Nugent,
E.Casale,
A.Cameron,
M.Ciomei,
F.Roletto,
A.Isacchi,
G.Fogliatto,
E.Pesenti,
W.Pastori,
A.Marsiglio,
K.L.Leach,
P.M.Clare,
F.Fiorentini,
M.Varasi,
A.Vulpetti,
M.A.Warpehoski.
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ABSTRACT
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Abnormal proliferation mediated by disruption of the normal cell cycle
mechanisms is a hallmark of virtually all cancer cells. Compounds targeting
complexes between cyclin-dependent kinases (CDK) and cyclins, such as
CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are
regarded as promising antitumor agents to complement the existing therapies.
From a high-throughput screening effort, we identified a new class of
CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is
described. X-ray crystallographic data of early compounds in this series, as
well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to
a nanomolar inhibitor of CDK2/cyclin A
(N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137,
IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse
xenograft model at a dose devoid of toxic effects.
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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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J.Xiang,
H.Yang,
C.Che,
H.Zou,
H.Yang,
Y.Wei,
J.Quan,
H.Zhang,
Z.Yang,
and
S.Lin
(2009).
Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays.
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PLoS ONE,
4,
e4361.
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M.Anzaldi,
C.Macciò,
M.Mazzei,
M.Bertolotto,
L.Ottonello,
F.Dallegri,
and
A.Balbi
(2009).
Antiproliferative and proapoptotic activities of a new class of pyrazole derivatives in HL-60 cells.
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Chem Biodivers,
6,
1674-1687.
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Z.Tang,
S.Jiang,
R.Du,
E.T.Petri,
A.El-Telbany,
P.S.Chan,
T.Kijima,
S.Dietrich,
K.Matsui,
M.Kobayashi,
S.Sasada,
N.Okamoto,
H.Suzuki,
K.Kawahara,
T.Iwasaki,
K.Nakagawa,
I.Kawase,
J.G.Christensen,
T.Hirashima,
B.Halmos,
R.Salgia,
T.J.Boggon,
J.A.Kern,
and
P.C.Ma
(2009).
Disruption of the EGFR E884-R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity.
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Oncogene,
28,
518-533.
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A.Montagnoli,
B.Valsasina,
V.Croci,
M.Menichincheri,
S.Rainoldi,
V.Marchesi,
M.Tibolla,
P.Tenca,
D.Brotherton,
C.Albanese,
V.Patton,
R.Alzani,
A.Ciavolella,
F.Sola,
A.Molinari,
D.Volpi,
N.Avanzi,
F.Fiorentini,
M.Cattoni,
S.Healy,
D.Ballinari,
E.Pesenti,
A.Isacchi,
J.Moll,
A.Bensimon,
E.Vanotti,
and
C.Santocanale
(2008).
A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity.
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Nat Chem Biol,
4,
357-365.
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D.M.Goldstein,
N.S.Gray,
and
P.P.Zarrinkar
(2008).
High-throughput kinase profiling as a platform for drug discovery.
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Nat Rev Drug Discov,
7,
391-397.
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G.Piersanti,
L.Giorgi,
F.Bartoccini,
G.Tarzia,
P.Minetti,
G.Gallo,
F.Giorgi,
M.Castorina,
O.Ghirardi,
and
P.Carminati
(2007).
Synthesis of benzo[1,2-d;3,4-d']diimidazole and 1H-pyrazolo[4,3-b]pyridine as putative A2A receptor antagonists.
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Org Biomol Chem,
5,
2567-2571.
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M.G.Brasca,
C.Albanese,
R.Amici,
D.Ballinari,
L.Corti,
V.Croci,
D.Fancelli,
F.Fiorentini,
M.Nesi,
P.Orsini,
F.Orzi,
W.Pastori,
E.Perrone,
E.Pesenti,
P.Pevarello,
F.Riccardi-Sirtori,
F.Roletto,
P.Roussel,
M.Varasi,
A.Vulpetti,
and
C.Mercurio
(2007).
6-Substituted Pyrrolo[3,4-c]pyrazoles: An Improved Class of CDK2 Inhibitors.
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ChemMedChem,
2,
841-852.
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A.Oloumi,
S.Syam,
and
S.Dedhar
(2006).
Modulation of Wnt3a-mediated nuclear beta-catenin accumulation and activation by integrin-linked kinase in mammalian cells.
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Oncogene,
25,
7747-7757.
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H.González-Díaz,
D.Viña,
L.Santana,
E.de Clercq,
and
E.Uriarte
(2006).
Stochastic entropy QSAR for the in silico discovery of anticancer compounds: prediction, synthesis, and in vitro assay of new purine carbanucleosides.
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Bioorg Med Chem,
14,
1095-1107.
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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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S.Bajaj,
S.S.Sambi,
and
A.K.Madan
(2005).
Topochemical models for prediction of anti-tumor activity of 3-aminopyrazoles.
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Chem Pharm Bull (Tokyo),
53,
611-615.
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B.Valsasina,
H.M.Kalisz,
and
A.Isacchi
(2004).
Kinase selectivity profiling by inhibitor affinity chromatography.
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Expert Rev Proteomics,
1,
303-315.
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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
