Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112

Liwei Chen, Daniele Pernazza, Latanya M. Scott, Harshani R. Lawrence, Yuan Ren, Yunting Luo, Xin Wu, Shen-shu Sung, Wayne C. Guida, Said M. Sebti, Nicholas J. Lawrence, Jie Wu

Research output: Contribution to journalArticle

26 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)801-810
Number of pages10
JournalBiochemical Pharmacology
Issue number6
StatePublished - Sep 1 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Fingerprint Dive into the research topics of 'Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112'. Together they form a unique fingerprint.

  • Cite this

    Chen, L., Pernazza, D., Scott, L. M., Lawrence, H. R., Ren, Y., Luo, Y., Wu, X., Sung, S., Guida, W. C., Sebti, S. M., Lawrence, N. J., & Wu, J. (2010). Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112. Biochemical Pharmacology, 80(6), 801-810.