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PDBsum entry 4hcu
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Transferase/transferase inhibitor
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PDB id
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4hcu
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References listed in PDB file
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Key reference
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Title
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Covalent inhibitors of interleukin-2 inducible t cell kinase (itk) with nanomolar potency in a whole-Blood assay.
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Authors
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C.W.Zapf,
B.S.Gerstenberger,
L.Xing,
D.C.Limburg,
D.R.Anderson,
N.Caspers,
S.Han,
A.Aulabaugh,
R.Kurumbail,
S.Shakya,
X.Li,
V.Spaulding,
R.M.Czerwinski,
N.Seth,
Q.G.Medley.
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Ref.
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J Med Chem, 2012,
55,
10047-10063.
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PubMed id
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Abstract
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We wish to report a strategy that targets interleukin-2inducible T cell kinase
(Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not
been disclosed in the literature. Structure-based drug design was utilized to
achieve low nanomolar potency of the disclosed series even at high ATP
concentrations. Kinetic measurements confirmed an irreversible binding mode with
off-rate half-lives exceeding 24 h and moderate on-rates. The analogues are
highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB)
assay. Despite a half-life of approximately 2 h in resting primary T cells, the
covalent inhibition of Itk resulted in functional silencing of the TCR pathway
for more than 24 h. This prolonged effect indicates that covalent inhibition is
a viable strategy to target the inactivation of Itk.
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