PDBsum entry 3o5x

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Hydrolase PDB id
Protein chain
255 a.a.
Waters ×134

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Key reference
Title Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (shp2).
Authors 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.Zha.
Ref. J.Med.Chem., 2010, 53, 2482-2493.
PubMed id 20170098
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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