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PDBsum entry 2bmc
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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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Aurora-2 t287d t288d complexed with pha-680632
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Structure:
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Serine threonine-protein kinase 6. Chain: a, b, c, d, e, f. Fragment: catalytic domain, residues 100-403. Synonym: aurora-a, serine/threonine kinase 15, aurora/ipl1-related kinase 1, aurora-related kinase 1, hark1, breast-tumor-amplified kinase. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: high five.
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Biol. unit:
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Dimer (from PDB file)
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Resolution:
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2.60Å
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R-factor:
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0.228
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R-free:
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0.252
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Authors:
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A.D.Cameron,G.Izzo,A.Sagliano,L.Rusconi,P.Storici,D.Fancelli,D.Berta, S.Bindi,C.Catana,B.Forte,P.Giordano,S.Mantegani,M.Meroni,J.Moll, V.Pittala,D.Severino,R.Tonani,M.Varasi,A.Vulpetti,P.Vianello
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Key ref:
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D.Fancelli
et al.
(2005).
Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition.
J Med Chem,
48,
3080-3084.
PubMed id:
DOI:
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Date:
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11-Mar-05
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Release date:
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17-Mar-05
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PROCHECK
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Headers
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References
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O14965
(AURKA_HUMAN) -
Aurora kinase A from Homo sapiens
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Seq:
Struc:
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403 a.a.
256 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.2.7.11.1
- 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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J Med Chem
48:3080-3084
(2005)
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PubMed id:
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Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition.
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D.Fancelli,
D.Berta,
S.Bindi,
A.Cameron,
P.Cappella,
P.Carpinelli,
C.Catana,
B.Forte,
P.Giordano,
M.L.Giorgini,
S.Mantegani,
A.Marsiglio,
M.Meroni,
J.Moll,
V.Pittalà,
F.Roletto,
D.Severino,
C.Soncini,
P.Storici,
R.Tonani,
M.Varasi,
A.Vulpetti,
P.Vianello.
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ABSTRACT
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Potent and selective Aurora kinase inhibitors were identified from the
combinatorial expansion of the 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
bi-cycle, a novel and versatile scaffold designed to target the ATP pocket of
protein kinases. The most potent compound reported in this study had an IC(50)
of 0.027 microM in the enzymatic assay for Aur-A inhibition and IC(50)s between
0.05 microM and 0.5 microM for the inhibition of proliferation of different
tumor cell lines.
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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.M.Chen,
and
H.Zhao
(2012).
(E)-3,3'-(Diazene-1,2-di-yl)bis-(1-methyl-1,4,5,6-tetra-hydro-pyrrolo-[3,4-c]pyrazol-5-ium) dinitrate dihydrate.
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Acta Crystallogr Sect E Struct Rep Online,
68,
o151.
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X.G.Bai,
J.X.Wang,
and
Y.C.Wang
(2012).
N-(1-Acetyl-5-benzoyl-1,4,5,6-tetra-hydro-pyrrolo-[3,4-c]pyrazol-3-yl)benzamide.
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Acta Crystallogr Sect E Struct Rep Online,
68,
o1677.
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A.Yan,
L.Wang,
S.Xu,
and
J.Xu
(2011).
Aurora-A kinase inhibitor scaffolds and binding modes.
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Drug Discov Today,
16,
260-269.
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W.B.Xia,
X.G.Bai,
H.T.Liu,
and
J.X.Wang
(2011).
5-tert-Butyl 1-ethyl 3-amino-1,4,5,6-tetra-hydro-pyrrolo-[3,4-c]pyrazole-1,5-dicarboxyl-ate.
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Acta Crystallogr Sect E Struct Rep Online,
67,
o1150.
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X.G.Bai,
H.T.Liu,
Y.C.Wang,
and
J.X.Wang
(2011).
3-(5-Chloro-naphthalene-1-sulfonamido)-2-(2-hy-droxy-eth-yl)-4,5,6,7-tetra-hydro-2H-pyrazolo-[4,3-c]pyridin-5-ium chloride.
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Acta Crystallogr Sect E Struct Rep Online,
67,
o1103.
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G.Görgün,
E.Calabrese,
T.Hideshima,
J.Ecsedy,
G.Perrone,
M.Mani,
H.Ikeda,
G.Bianchi,
Y.Hu,
D.Cirstea,
L.Santo,
Y.T.Tai,
S.Nahar,
M.Zheng,
M.Bandi,
R.D.Carrasco,
N.Raje,
N.Munshi,
P.Richardson,
and
K.C.Anderson
(2010).
A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma.
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Blood,
115,
5202-5213.
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R.E.Kleiner,
C.E.Dumelin,
G.C.Tiu,
K.Sakurai,
and
D.R.Liu
(2010).
In vitro selection of a DNA-templated small-molecule library reveals a class of macrocyclic kinase inhibitors.
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J Am Chem Soc,
132,
11779-11791.
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X.Guo,
X.G.Bai,
Y.L.Li,
and
Y.C.Wang
(2010).
tert-Butyl 3-amino-2-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxyl-ate.
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Acta Crystallogr Sect E Struct Rep Online,
66,
o1108.
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D.Demidov,
S.Hesse,
A.Tewes,
T.Rutten,
J.Fuchs,
R.K.Ashtiyani,
S.Lein,
A.Fischer,
G.Reuter,
and
A.Houben
(2009).
Aurora1 phosphorylation activity on histone H3 and its cross-talk with other post-translational histone modifications in Arabidopsis.
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Plant J,
59,
221-230.
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N.Jetton,
K.G.Rothberg,
J.G.Hubbard,
J.Wise,
Y.Li,
H.L.Ball,
and
L.Ruben
(2009).
The cell cycle as a therapeutic target against Trypanosoma brucei: Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms.
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Mol Microbiol,
72,
442-458.
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T.M.Bandeiras,
R.C.Hillig,
P.M.Matias,
U.Eberspaecher,
J.Fanghänel,
M.Thomaz,
S.Miranda,
K.Crusius,
V.Pütter,
P.Amstutz,
M.Gulotti-Georgieva,
H.K.Binz,
C.Holz,
A.A.Schmitz,
C.Lang,
P.Donner,
U.Egner,
M.A.Carrondo,
and
B.Müller-Tiemann
(2008).
Structure of wild-type Plk-1 kinase domain in complex with a selective DARPin.
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Acta Crystallogr D Biol Crystallogr,
64,
339-353.
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PDB code:
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X.Q.Deng,
H.Y.Wang,
Y.L.Zhao,
M.L.Xiang,
P.D.Jiang,
Z.X.Cao,
Y.Z.Zheng,
S.D.Luo,
L.T.Yu,
Y.Q.Wei,
and
S.Y.Yang
(2008).
Pharmacophore modelling and virtual screening for identification of new Aurora-A kinase inhibitors.
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Chem Biol Drug Des,
71,
533-539.
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K.Hoar,
A.Chakravarty,
C.Rabino,
D.Wysong,
D.Bowman,
N.Roy,
and
J.A.Ecsedy
(2007).
MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy.
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Mol Cell Biol,
27,
4513-4525.
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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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M.G.Manfredi,
J.A.Ecsedy,
K.A.Meetze,
S.K.Balani,
O.Burenkova,
W.Chen,
K.M.Galvin,
K.M.Hoar,
J.J.Huck,
P.J.LeRoy,
E.T.Ray,
T.B.Sells,
B.Stringer,
S.G.Stroud,
T.J.Vos,
G.S.Weatherhead,
D.R.Wysong,
M.Zhang,
J.B.Bolen,
and
C.F.Claiborne
(2007).
Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase.
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Proc Natl Acad Sci U S A,
104,
4106-4111.
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M.Schmidt,
and
H.Bastians
(2007).
Mitotic drug targets and the development of novel anti-mitotic anticancer drugs.
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Drug Resist Updat,
10,
162-181.
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T.Persson,
C.W.Yde,
J.E.Rasmussen,
T.L.Rasmussen,
B.Guerra,
O.G.Issinger,
and
J.Nielsen
(2007).
Pyrazole carboxamides and carboxylic acids as protein kinase inhibitors in aberrant eukaryotic signal transduction: induction of growth arrest in MCF-7 cancer cells.
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Org Biomol Chem,
5,
3963-3970.
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N.Matthews,
C.Visintin,
B.Hartzoulakis,
A.Jarvis,
and
D.L.Selwood
(2006).
Aurora A and B kinases as targets for cancer: will they be selective for tumors?
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Expert Rev Anticancer Ther,
6,
109-120.
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S.Fu,
W.Hu,
J.J.Kavanagh,
and
R.C.Bast
(2006).
Targeting Aurora kinases in ovarian cancer.
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Expert Opin Ther Targets,
10,
77-85.
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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
