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Salicylic Acid Based Small Molecule Inhibitor for the Oncogenic Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2)

2010; American Chemical Society; Volume: 53; Issue: 6 Linguagem: Inglês

10.1021/jm901645u

1520-4804

Xian Zhang, Yantao He, Sijiu Liu, Zhihong Yu, Zhong‐Xing Jiang, Zhenyun Yang, Yuanshu Dong, Sarah C. Nabinger, Li Wu, Andrea Gunawan, Lina Wang, Rebecca J. Chan, Zhong‐Yin Zhang,

PI3K/AKT/mTOR signaling in cancer

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.