Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112.
Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112.
复制标题
DOI：
10.1016/j.bcp.2010.05.019
复制
发表时间：
2010-09-15
影响因子：
5.8
通讯作者：
Wu, Jie
中科院分区：
文献类型：
--
作者：
Chen, Liwei;Pernazza, Daniele;Scott, Latanya M.;Lawrence, Harshani R.;Ren, Yuan;Luo, Yunting;Wu, Xin;Sung, Shen-Shu;Guida, Wayne C.;Sebti, Said M.;Lawrence, Nicholas J.;Wu, Jie
The protein tyrosine phosphatase (PTP) Shp2 (PTPN11) is an attractive target for anticancer drug discovery because it mediates growth factor signaling and its gain-of-function mutants are causally linked to leukemias. We previously synthesized SPI-112 from a lead compound of Shp2 inhibitor, NSC-117199. In this study, we demonstrated that SPI-112 bound to Shp2 by surface plasmon resonance (SPR) and displayed competitive inhibitor kinetics to Shp2. Like some other compounds in the PTP inhibitor discovery efforts, SPI-112 was not cell permeable, precluding its use in biological studies. To overcome the cell permeation issue, we prepared a methyl ester SPI-112 analog (SPI-112Me) that is predicted to be hydrolyzed to SPI-112 upon entry into cells. Fluorescence uptake assay and confocal imaging suggested that SPI-112Me was taken up by cells. Incubation of cells with SPI-112Me inhibited epidermal growth factor (EGF)-stimulated Shp2 PTP activity and Shp2-mediated paxillin dephosphorylation, Erk1/2 activation, and cell migration. SPI-112Me treatment also inhibited Erk1/2 activation by a Gab1-Shp2 chimera. Treatment of Shp2E76K mutant-transformed TF-1 myeloid cells with SPI-112Me resulted in inhibition of Shp2E76K-dependent cell survival, which is associated with inhibition of Shp2E76K PTP activity, Shp2E76K-induced Erk1/2 activation, and Bcl-XL expression. Furthermore, SPI-112Me enhanced interferon-γ (IFN-γ)-stimulated STAT1 tyrosine phosphorylation, ISRE-luciferase reporter activity, p21 expression, and the anti-proliferative effect. Thus, the SPI-112 methyl ester analog was able to inhibit cellular Shp2 PTP activity.
登录
查看更多内容
影响因子：
5.5
作者：
Chatterjee, Prodyot K.;Al-Abed, Yousef;Metz, Christine N.
通讯作者：
Metz, Christine N.
影响因子：
4.8
作者：
Cunnick, JM;Meng, SS;Wu, J
通讯作者：
Wu, J
影响因子：
20.3
作者：
Kratz, CP;Niemeyer, CM;Loh, ML
通讯作者：
Loh, ML
影响因子：
56.9
作者：
Chin, YE;Kitagawa, M;Fu, XY
通讯作者：
Fu, XY
影响因子：
11.2
作者：
Mulloy, Roseann;Ferrand, Audrey;Settleman, Jeffrey
通讯作者：
Settleman, Jeffrey