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

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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. Indiana-Med
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002587
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 53; Journal Issue: (6) ; 03, 2010; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 98 NUCLEAR DISARMAMENT, SAFEGUARDS, AND PHYSICAL PROTECTION; AFFINITY; GROWTH FACTORS; LYMPHOKINES; MUTATIONS; NEOPLASMS; PROLIFERATION; PROTEINS; SALICYLIC ACID; TARGETS; THERAPY; TYROSINE

Citation Formats

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, and Zhang, Zhong-Yin. Salicylic Acid Based Small Molecule Inhibitor for the Oncogenic Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2). United States: N. p., 2010. Web. doi: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). United States. 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, and Zhang, Zhong-Yin. Fri . "Salicylic Acid Based Small Molecule Inhibitor for the Oncogenic Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2)". United States. https://doi.org/10.1021/jm901645u.
@article{osti_1002587,
title = {Salicylic Acid Based Small Molecule Inhibitor for the Oncogenic Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2)},
author = {Zhang, Xian and He, Yantao and Liu, Sijiu and Yu, Zhihong and Jiang, Zhong-Xing and Yang, Zhenyun and Dong, Yuanshu and Nabinger, Sarah C and Wu, Li and Gunawan, Andrea M and Wang, Lina and Chan, Rebecca J and Zhang, Zhong-Yin},
abstractNote = {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.},
doi = {10.1021/jm901645u},
url = {https://www.osti.gov/biblio/1002587}, journal = {J. Med. Chem.},
issn = {0022-2623},
number = (6) ; 03, 2010,
volume = 53,
place = {United States},
year = {2010},
month = {8}
}