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PDBsum entry 4fyn
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Transferase/transferase inhibitor
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PDB id
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4fyn
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References listed in PDB file
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Key reference
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Title
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Rational design of highly selective spleen tyrosine kinase inhibitors.
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Authors
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M.C.Lucas,
D.M.Goldstein,
J.C.Hermann,
A.Kuglstatter,
W.Liu,
K.C.Luk,
F.Padilla,
M.Slade,
A.G.Villaseñor,
J.Wanner,
W.Xie,
X.Zhang,
C.Liao.
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Ref.
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J Med Chem, 2012,
55,
10414-10423.
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PubMed id
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Abstract
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A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is
described. Inhibition of spleen tyrosine kinase has attracted much attention as
a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid
arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed
phase II clinical trials, also exhibits some undesirable side effects. More
selective Syk inhibitors could offer safer, alternative treatments. Through a
systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk
ATP binding site as a rare combination among sequence aligned kinases and
hypothesized that optimizing the interaction between them and a Syk inhibitor
molecule would impart high selectivity for Syk over other kinases. We report the
structure-guided identification of three series of selective spleen tyrosine
kinase inhibitors that support our hypothesis and offer useful guidance to other
researchers in the field.
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