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PDBsum entry 2x6d
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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-a bound to an inhibitor
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Structure:
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Serine/threonine-protein kinase 6. Chain: a. Fragment: catalytic domain, residues 122-403. Synonym: aurora-a, aurora kinase a, serine/threonine-protein kinase aurora-a, serine/threonine kinase 15, aurora/ipl1-related kinase 1, aurora-related kinase 1, ark-1, hark-1, breast tumor-amplified kinase. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.80Å
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R-factor:
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0.220
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R-free:
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0.264
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Authors:
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M.Kosmopoulou,R.Bayliss
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Key ref:
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V.Bavetsias
et al.
(2010).
Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: lead optimization studies toward the identification of an orally bioavailable preclinical development candidate.
J Med Chem,
53,
5213-5228.
PubMed id:
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Date:
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17-Feb-10
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Release date:
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07-Jul-10
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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.
255 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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J Med Chem
53:5213-5228
(2010)
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PubMed id:
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Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: lead optimization studies toward the identification of an orally bioavailable preclinical development candidate.
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V.Bavetsias,
J.M.Large,
C.Sun,
N.Bouloc,
M.Kosmopoulou,
M.Matteucci,
N.E.Wilsher,
V.Martins,
J.Reynisson,
B.Atrash,
A.Faisal,
F.Urban,
M.Valenti,
A.de Haven Brandon,
G.Box,
F.I.Raynaud,
P.Workman,
S.A.Eccles,
R.Bayliss,
J.Blagg,
S.Linardopoulos,
E.McDonald.
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ABSTRACT
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Lead optimization studies using 7 as the starting point led to a new class of
imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the
1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro
properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear
understanding into the interactions of this novel class of inhibitors with the
Aurora kinases. Subsequent physicochemical property refinement by the
incorporation of solubilizing groups led to the identification of
3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole
(51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC(50) =
0.015 +/- 0.003 muM, Aurora-B IC(50) = 0.025 muM, Aurora-C IC(50) = 0.019 muM).
Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it
inhibited the growth of SW620 colon carcinoma xenografts following oral
administration with no observed toxicities as defined by body weight loss.
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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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L.L.Yang,
R.L.Zheng,
G.B.Li,
Q.Z.Sun,
and
Y.M.Xie
(2011).
4-(4-Nitro-benz-yl)morpholine.
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Acta Crystallogr Sect E Struct Rep Online,
67,
o754.
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S.Dahmani,
Y.Kandri Rodi,
S.V.Luis,
M.Bolte,
and
L.El Ammari
(2011).
1,3-Diallyl-6-bromo-1H-imidazo[4,5-b]pyridin-2(3H)-one.
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Acta Crystallogr Sect E Struct Rep Online,
67,
o1986.
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S.Dahmani,
Y.Kandri Rodi,
S.V.Luis,
M.Bolte,
and
L.El Ammari
(2011).
3-Allyl-6-bromo-1H-imidazo[4,5-b]pyridin-2(3H)-one.
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Acta Crystallogr Sect E Struct Rep Online,
67,
o1998.
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X.Y.Qing,
Y.C.Huang,
L.L.Yang,
and
Y.M.Xie
(2011).
6-Chloro-3-nitro-N-(propan-2-yl)pyridin-2-amine.
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Acta Crystallogr Sect E Struct Rep Online,
67,
o1480.
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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
