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PDBsum entry 4pv0
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Transferase/transferase inhibitor
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PDB id
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4pv0
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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 of gs-9973, A selective and orally efficacious inhibitor of spleen tyrosine kinase.
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Authors
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K.S.Currie,
J.E.Kropf,
T.Lee,
P.Blomgren,
J.Xu,
Z.Zhao,
S.Gallion,
J.A.Whitney,
D.Maclin,
E.B.Lansdon,
P.Maciejewski,
A.M.Rossi,
H.Rong,
J.Macaluso,
J.Barbosa,
J.A.Di paolo,
S.A.Mitchell.
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Ref.
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J Med Chem, 2014,
57,
3856-3873.
[DOI no: ]
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PubMed id
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Abstract
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Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune,
inflammatory, and oncology disease indications. The most advanced Syk inhibitor,
R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple
therapeutic indications, but its clinical progress has been hampered by
dose-limiting adverse effects that have been attributed, at least in part, to
the off-target activities of 1. It is expected that a more selective Syk
inhibitor would provide a greater therapeutic window. Herein we report the
discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk
inhibitors. This work culminated in the identification of GS-9973, 68, a highly
selective and orally efficacious Syk inhibitor which is currently undergoing
clinical evaluation for autoimmune and oncology indications.
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