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PDBsum entry 2o63
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Contents |
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* Residue conservation analysis
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Enzyme class:
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E.C.2.7.11.1
- non-specific serine/threonine protein 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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Mol Cancer Ther
6:163-172
(2007)
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PubMed id:
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Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase.
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S.Holder,
M.Zemskova,
C.Zhang,
M.Tabrizizad,
R.Bremer,
J.W.Neidigh,
M.B.Lilly.
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ABSTRACT
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The pim-1 kinase is a true oncogene that has been implicated in the development
of leukemias, lymphomas, and prostate cancer, and is the target of drug
development programs. We have used experimental approaches to identify a
selective, cell-permeable, small-molecule inhibitor of the pim-1 kinase to
foster basic and translational studies of the enzyme. We used an ELISA-based
kinase assay to screen a diversity library of potential kinase inhibitors. The
flavonol quercetagetin (3,3',4',5,6,7-hydroxyflavone) was identified as a
moderately potent, ATP-competitive inhibitor (IC(50), 0.34 micromol/L).
Resolution of the crystal structure of PIM1 in complex with quercetagetin or two
other flavonoids revealed a spectrum of binding poses and hydrogen-bonding
patterns in spite of strong similarity of the ligands. Quercetagetin was a
highly selective inhibitor of PIM1 compared with PIM2 and seven other
serine-threonine kinases. Quercetagetin was able to inhibit PIM1 activity in
intact RWPE2 prostate cancer cells in a dose-dependent manner (ED(50), 5.5
micromol/L). RWPE2 cells treated with quercetagetin showed pronounced growth
inhibition at inhibitor concentrations that blocked PIM1 kinase activity.
Furthermore, the ability of quercetagetin to inhibit the growth of other
prostate epithelial cell lines varied in proportion to their levels of PIM1
protein. Quercetagetin can function as a moderately potent and selective,
cell-permeable inhibitor of the pim-1 kinase, and may be useful for
proof-of-concept studies to support the development of clinically useful PIM1
inhibitors.
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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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D.Morishita,
M.Takami,
S.Yoshikawa,
R.Katayama,
S.Sato,
M.Kukimoto-Niino,
T.Umehara,
M.Shirouzu,
K.Sekimizu,
S.Yokoyama,
and
N.Fujita
(2011).
Cell-permeable carboxyl-terminal p27(Kip1) peptide exhibits anti-tumor activity by inhibiting Pim-1 kinase.
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J Biol Chem,
286,
2681-2688.
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PDB code:
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B.Wright,
L.A.Moraes,
C.F.Kemp,
W.Mullen,
A.Crozier,
J.A.Lovegrove,
and
J.M.Gibbins
(2010).
A structural basis for the inhibition of collagen-stimulated platelet function by quercetin and structurally related flavonoids.
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Br J Pharmacol,
159,
1312-1325.
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K.Nihira,
Y.Ando,
T.Yamaguchi,
Y.Kagami,
Y.Miki,
and
K.Yoshida
(2010).
Pim-1 controls NF-kappaB signalling by stabilizing RelA/p65.
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Cell Death Differ,
17,
689-698.
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L.Brault,
C.Gasser,
F.Bracher,
K.Huber,
S.Knapp,
and
J.Schwaller
(2010).
PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers.
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Haematologica,
95,
1004-1015.
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M.Willert,
A.Augstein,
D.M.Poitz,
A.Schmeisser,
R.H.Strasser,
and
R.C.Braun-Dullaeus
(2010).
Transcriptional regulation of Pim-1 kinase in vascular smooth muscle cells and its role for proliferation.
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Basic Res Cardiol,
105,
267-277.
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N.Dzamko,
M.Deak,
F.Hentati,
A.D.Reith,
A.R.Prescott,
D.R.Alessi,
and
R.J.Nichols
(2010).
Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization.
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Biochem J,
430,
405-413.
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N.M.Santio,
R.L.Vahakoski,
E.M.Rainio,
J.A.Sandholm,
S.S.Virtanen,
M.Prudhomme,
F.Anizon,
P.Moreau,
and
P.J.Koskinen
(2010).
Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion.
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Mol Cancer,
9,
279.
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N.S.Magnuson,
Z.Wang,
G.Ding,
and
R.Reeves
(2010).
Why target PIM1 for cancer diagnosis and treatment?
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Future Oncol,
6,
1461-1478.
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K.M.Gust,
M.D.Hofer,
S.R.Perner,
R.Kim,
A.M.Chinnaiyan,
S.Varambally,
P.Moller,
L.Rinnab,
M.A.Rubin,
J.Greiner,
M.Schmitt,
R.Kuefer,
and
M.Ringhoffer
(2009).
RHAMM (CD168) is overexpressed at the protein level and may constitute an immunogenic antigen in advanced prostate cancer disease.
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Neoplasia,
11,
956-963.
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K.Peltola,
M.Hollmen,
S.M.Maula,
E.Rainio,
R.Ristamäki,
M.Luukkaa,
J.Sandholm,
M.Sundvall,
K.Elenius,
P.J.Koskinen,
R.Grenman,
and
S.Jalkanen
(2009).
Pim-1 kinase expression predicts radiation response in squamocellular carcinoma of head and neck and is under the control of epidermal growth factor receptor.
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Neoplasia,
11,
629-636.
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S.M.Mumenthaler,
P.Y.Ng,
A.Hodge,
D.Bearss,
G.Berk,
S.Kanekal,
S.Redkar,
P.Taverna,
D.B.Agus,
and
A.Jain
(2009).
Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes.
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Mol Cancer Ther,
8,
2882-2893.
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E.D.Hsi,
S.H.Jung,
R.Lai,
J.L.Johnson,
J.R.Cook,
D.Jones,
S.Devos,
B.D.Cheson,
L.E.Damon,
and
J.Said
(2008).
Ki67 and PIM1 expression predict outcome in mantle cell lymphoma treated with high dose therapy, stem cell transplantation and rituximab: a Cancer and Leukemia Group B 59909 correlative science study.
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Leuk Lymphoma,
49,
2081-2090.
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J.R.Gledhill,
M.G.Montgomery,
A.G.Leslie,
and
J.E.Walker
(2007).
Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols.
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Proc Natl Acad Sci U S A,
104,
13632-13637.
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PDB codes:
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W.A.Peer,
and
A.S.Murphy
(2007).
Flavonoids and auxin transport: modulators or regulators?
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Trends Plant Sci,
12,
556-563.
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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.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
