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PDBsum entry 3o5x
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References listed in PDB file
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Key reference
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Title
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Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (shp2).
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Authors
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X.Zhang,
Y.He,
S.Liu,
Z.Yu,
Z.X.Jiang,
Z.Yang,
Y.Dong,
S.C.Nabinger,
L.Wu,
A.M.Gunawan,
L.Wang,
R.J.Chan,
Z.Y.Zhang.
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Ref.
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J Med Chem, 2010,
53,
2482-2493.
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PubMed id
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Abstract
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The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays
a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2
mutations are associated with Noonan syndrome, various kinds of leukemias, and
solid tumors. Thus, there is considerable interest in SHP2 as a potential target
for anticancer and antileukemia therapy. We report a salicylic acid based
combinatorial library approach aimed at binding both active site and unique
nearby subpockets for enhanced affinity and selectivity. Screening of the
library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with
highly efficacious cellular activity. Compound 9 blocks growth factor stimulated
ERK1/2 activation and hematopoietic progenitor proliferation, providing
supporting evidence that chemical inhibition of SHP2 may be therapeutically
useful for anticancer and antileukemia treatment. X-ray crystallographic
analysis of the structure of SHP2 in complex with 9 reveals molecular
determinants that can be exploited for the acquisition of more potent and
selective SHP2 inhibitors.
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