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PDBsum entry 4ppb
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Transferase/transferase inhibitor
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PDB id
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4ppb
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References listed in PDB file
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Key reference
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Title
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Discovery and optimization of indazoles as potent and selective interleukin-2 inducible t cell kinase (itk) inhibitors.
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Authors
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R.M.Pastor,
J.D.Burch,
S.Magnuson,
D.F.Ortwine,
Y.Chen,
K.De la torre,
X.Ding,
C.Eigenbrot,
A.Johnson,
M.Liimatta,
Y.Liu,
S.Shia,
X.Wang,
L.C.Wu,
Z.Pei.
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Ref.
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Bioorg Med Chem Lett, 2014,
24,
2448-2452.
[DOI no: ]
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PubMed id
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Abstract
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There is evidence that small molecule inhibitors of the non-receptor tyrosine
kinase ITK, a component of the T-cell receptor signaling cascade, could
represent a novel asthma therapeutic class. Moreover, given the expected chronic
dosing regimen of any asthma treatment, highly selective as well as potent
inhibitors would be strongly preferred in any potential therapeutic. Here we
report hit-to-lead optimization of a series of indazoles that demonstrate
sub-nanomolar inhibitory potency against ITK with strong cellular activity and
good kinase selectivity. We also elucidate the binding mode of these inhibitors
by solving the X-ray crystal structures of the complexes.
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