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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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Crystal structure of aminoquinazoline 1 bound to lck
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Structure:
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Proto-oncogene tyrosine-protein kinase lck. Chain: a, b. Fragment: lck kinase domain, residues 231-497. Synonym: p56-lck, lymphocyte cell-specific protein-tyrosine kinase, lsk, t cell- specific protein-tyrosine kinase. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: lck. Expressed in: insect cell.
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Resolution:
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2.00Å
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R-factor:
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0.274
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R-free:
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0.301
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Authors:
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X.Huang
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Key ref:
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E.F.DiMauro
et al.
(2006).
Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity.
J Med Chem,
49,
5671-5686.
PubMed id:
DOI:
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Date:
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04-Jan-07
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Release date:
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27-Feb-07
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PROCHECK
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Headers
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References
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Enzyme class:
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Chains A, B:
E.C.2.7.10.2
- non-specific protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[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
49:5671-5686
(2006)
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PubMed id:
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Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity.
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E.F.DiMauro,
J.Newcomb,
J.J.Nunes,
J.E.Bemis,
C.Boucher,
J.L.Buchanan,
W.H.Buckner,
V.J.Cee,
L.Chai,
H.L.Deak,
L.F.Epstein,
T.Faust,
P.Gallant,
S.D.Geuns-Meyer,
A.Gore,
Y.Gu,
B.Henkle,
B.L.Hodous,
F.Hsieh,
X.Huang,
J.L.Kim,
J.H.Lee,
M.W.Martin,
C.E.Masse,
D.C.McGowan,
D.Metz,
D.Mohn,
K.A.Morgenstern,
A.Oliveira-dos-Santos,
V.F.Patel,
D.Powers,
P.E.Rose,
S.Schneider,
S.A.Tomlinson,
Y.Y.Tudor,
S.M.Turci,
A.A.Welcher,
R.D.White,
H.Zhao,
L.Zhu,
X.Zhu.
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ABSTRACT
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The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src
family expressed in T cells and natural killer (NK) cells. Genetic evidence in
both mice and humans demonstrates that Lck kinase activity is critical for
signaling mediated by the T cell receptor (TCR), which leads to normal T cell
development and activation. Selective inhibition of Lck is expected to offer a
new therapy for the treatment of T-cell-mediated autoimmune and inflammatory
disease. Screening of our kinase-preferred collection identified
aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell
proliferation. In this report, we describe the synthesis and structure-activity
relationships of a series of novel aminoquinazolines possessing in vitro
mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47
exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in
the anti-CD3-induced production of interleukin-2 (IL-2) in mice.
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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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P.Ranjitkar,
A.M.Brock,
and
D.J.Maly
(2010).
Affinity reagents that target a specific inactive form of protein kinases.
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Chem Biol,
17,
195-206.
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S.S.Bhagwat
(2009).
Kinase inhibitors for the treatment of inflammatory and autoimmune disorders.
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Purinergic Signal,
5,
107-115.
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V.M.Anisimov,
and
V.L.Bugaenko
(2009).
QM/QM docking method based on the variational finite localized molecular orbital approximation.
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J Comput Chem,
30,
784-798.
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W.Link,
J.Oyarzabal,
B.G.Serelde,
M.I.Albarran,
O.Rabal,
A.Cebriá,
P.Alfonso,
J.Fominaya,
O.Renner,
S.Peregrina,
D.Soilán,
P.A.Ceballos,
A.I.Hernández,
M.Lorenzo,
P.Pevarello,
T.G.Granda,
G.Kurz,
A.Carnero,
and
J.R.Bischoff
(2009).
Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases.
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J Biol Chem,
284,
28392-28400.
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A.C.Dar,
M.S.Lopez,
and
K.M.Shokat
(2008).
Small molecule recognition of c-Src via the Imatinib-binding conformation.
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Chem Biol,
15,
1015-1022.
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PDB codes:
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J.Won,
and
G.H.Lee
(2008).
T-cell-targeted signaling inhibitors.
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Int Rev Immunol,
27,
19-41.
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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
codes are
shown on the right.
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Links
