Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)

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

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2482-2493
Number of pages12
JournalJournal of Medicinal Chemistry
Volume53
Issue number6
DOIs
StatePublished - Mar 25 2010

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SH2 Domain-Containing Protein Tyrosine Phosphatases
Protein Phosphatase 2
Protein Tyrosine Phosphatases
Salicylic Acid
Intercellular Signaling Peptides and Proteins
Noonan Syndrome
Libraries
Catalytic Domain
Leukemia
X-Rays
Cytokines
Mutation
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). / Zhang, Xian; He, Yantao; Liu, Sijiu; Yu, Zhihong; Jiang, Zhong Xing; Yang, Zhenyun; Dong, Yuanshu; Nabinger, Sarah C.; Wu, Li; Gunawan, Andrea M.; Wang, Lina; Chan, Rebecca J.; Zhang, Zhong Yin.

In: Journal of Medicinal Chemistry, Vol. 53, No. 6, 25.03.2010, p. 2482-2493.

Research output: Contribution to journalArticle

Zhang, X, He, Y, Liu, S, Yu, Z, Jiang, ZX, Yang, Z, Dong, Y, Nabinger, SC, Wu, L, Gunawan, AM, Wang, L, Chan, RJ & Zhang, ZY 2010, 'Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)', Journal of Medicinal Chemistry, vol. 53, no. 6, pp. 2482-2493. https://doi.org/10.1021/jm901645u
Zhang, Xian ; He, Yantao ; Liu, Sijiu ; Yu, Zhihong ; Jiang, Zhong Xing ; Yang, Zhenyun ; Dong, Yuanshu ; Nabinger, Sarah C. ; Wu, Li ; Gunawan, Andrea M. ; Wang, Lina ; Chan, Rebecca J. ; Zhang, Zhong Yin. / Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 6. pp. 2482-2493.
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