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 language | English (US) |
|---|---|
| Pages (from-to) | 2482-2493 |
| Number of pages | 12 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 53 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 25 2010 |
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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 journal › Article
}
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 J.
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.
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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 -