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

Fingerprint

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; 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, R & Zhang, Z-Y 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 ; 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.
@article{531e40c12b274c3787207323a6086c4d,
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.",
author = "Xian Zhang and Yantao He and Sijiu Liu and Zhihong Yu and Jiang, {Zhong Xing} and Zhenyun Yang and Yuanshu Dong and Nabinger, {Sarah C.} and Li Wu and Gunawan, {Andrea M.} and Lina Wang and Rebecca Chan and Zhong-Yin Zhang",
year = "2010",
month = "3",
day = "25",
doi = "10.1021/jm901645u",
language = "English",
volume = "53",
pages = "2482--2493",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "6",

}

TY - JOUR

T1 - Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)

AU - Zhang, Xian

AU - He, Yantao

AU - Liu, Sijiu

AU - Yu, Zhihong

AU - Jiang, Zhong Xing

AU - Yang, Zhenyun

AU - Dong, Yuanshu

AU - Nabinger, Sarah C.

AU - Wu, Li

AU - Gunawan, Andrea M.

AU - Wang, Lina

AU - Chan, Rebecca

AU - Zhang, Zhong-Yin

PY - 2010/3/25

Y1 - 2010/3/25

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77949853380&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77949853380&partnerID=8YFLogxK

U2 - 10.1021/jm901645u

DO - 10.1021/jm901645u

M3 - Article

C2 - 20170098

AN - SCOPUS:77949853380

VL - 53

SP - 2482

EP - 2493

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 6

ER -