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

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

doi:10.1016/j.bcp.2010.05.019

Cited by 52 publications

(29 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SPI-112Me is a cell permeable Shp2 inhibitor [11, 24]. To further evaluate the role of Shp2 PTP activity in HCC827 and H1975 cells, we treated these cells with various concentrations of SPI-112Me.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma

et al. 2015

Self Cite

View full text Add to dashboard Cite

Epidermal growth factor receptor (EGFR) mutants drive lung tumorigenesis and are targeted for therapy. However, resistance to EGFR inhibitors has been observed, in which the mutant EGFR remains active. Thus, it is important to uncover mediators of EGFR mutant-driven lung tumors to develop new treatment strategies. The protein tyrosine phosphatase (PTP) Shp2 mediates EGF signaling. Nevertheless, it is unclear if Shp2 is activated by oncogenic EGFR mutants in lung carcinoma or if inhibiting the Shp2 PTP activity can suppress EGFR mutant-induced lung adenocarcinoma. Here, we generated transgenic mice containing a doxycycline (Dox)-inducible PTP-defective Shp2 mutant (tetO-Shp2CSDA). Using the rat Clara cell secretory protein (CCSP)-rtTA-directed transgene expression in the type II lung pneumocytes of transgenic mice, we found that the Gab1-Shp2 pathway was activated by EGFRL858R in the lungs of transgenic mice. Consistently, the Gab1-Shp2 pathway was activated in human lung adenocarcinoma cells containing mutant EGFR. Importantly, Shp2CSDA inhibited EGFRL858R-induced lung adenocarcinoma in transgenic animals. Analysis of lung tissues showed that Shp2CSDA suppressed Gab1 tyrosine phosphorylation and Gab1-Shp2 association, suggesting that Shp2 modulates a positive feedback loop to regulate its own activity. These results show that inhibition of the Shp2 PTP activity impairs mutant EGFR signaling and suppresses EGFRL858R-driven lung adenocarcinoma.

show abstract

Section: Resultsmentioning

confidence: 99%

“…WZ4002 was from Selleck. SPI-112Me was synthesized as described [11]. Antibodies to Shp2, Erk1/2, phospho-Erk1/2 (pErk1/2, T202/Y204), Gab1, Akt, c-Myc, and β-actin were obtained from Santa Cruz Biotechnology.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…To exclude a role for SHP1 in TLR3 expression pathway, we performed experiments with cell-active SHP2 selective inhibitor SPI-112Me (37). Real-time PCR analysis of TLR3 expression in MDDCs at day 5 of culture (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Data were normalized to the activity of Renilla luciferase. A549 cells were pretreated with SHP2 inhibitors NSC-87877 or SPI-112 Me (37) for 2 h then cotransfected with IRF-1, IRF-8, or combination of expressing vectors with the calcium phosphate method and 6 h later transfected with 20 μg/ml poly-IC–Fugene 6 complexes. Cells were collected 24 h after.…”

Section: Methodsmentioning

confidence: 99%

Critical Role of IRF-8 in Negative Regulation of TLR3 Expression by Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-2 Activity in Human Myeloid Dendritic Cells

Fragale

Stellacci

Ilari

et al. 2011

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Despite extensive studies that unraveled ligands and signal transduction pathways triggered by TLRs, little is known about the regulation of TLR gene expression. TLR3 plays a crucial role in the recognition of viral pathogens and induction of immune responses by myeloid DCs. IFN regulatory factor (IRF)-8, a member of the IRF family, is a transcriptional regulator that plays essential roles in the development and function of myeloid lineage, affecting different subsets of myeloid DCs. In this study, we show that IRF-8 negatively controls TLR3 gene expression by suppressing IRF-1– and/or polyinosinic-polycytidylic acid-stimulated TLR3 expression in primary human monocyte-derived DCs (MDDCs). MDDCs expressed TLR3 increasingly during their differentiation from monocytes to DCs with a peak at day 5, when TLR3 expression was further enhanced upon stimulation with polyinosinic-polycytidylic acid and then was promptly downregulated. We found that both IRF-1 and IRF-8 bind the human TLR3 promoter during MDDC differentiation in vitro and in vivo but with different kinetic and functional effects. We demonstrate that IRF-8–induced repression of TLR3 is specifically mediated by ligand-activated Src homology 2 domain-containing protein tyrosine phosphatase association. Indeed, Src homology 2 domain-containing protein tyrosine phosphatase–dephosphorylated IRF-8 bound to the human TLR3 promoter competing with IRF-1 and quashing its activity by recruitment of histone deacetylase 3. Our findings identify IRF-8 as a key player in the control of intracellular viral dsRNA-induced responses and highlight a new mechanism for negative regulation of TLR3 expression that can be exploited to block excessive TLR activation.

show abstract

“…But this compound was not cell permeable. To overcome this cell permeable issue the SPI-112 was converted to its methyl ester analog SPI-112Me (59) [107]. This methyl ester analog showed a inhibitor activity to EGF -stimulated Shp2 PTP activity, and Erk 1/2 activation, Shp2-mediated paxillin dephosphorylation.…”

Section: Protein Tyrosine Phosphatase (Shp2) Inhibitorsmentioning

confidence: 99%

Indolinones as Promising Scaffold as Kinase Inhibitors: A Review

Prakash¹,

Raja

2012

MRMC

View full text Add to dashboard Cite

Kinases are probably the most important signaling enzymes, which represent about 20% of the druggable genome. Currently, more than 150 kinases are known. So, kinase inhibition therapy has become a very important area of drug research since most of our diseases are related to intra or intercellular signaling by kinases. Indole alkaloids are extensively studied for their biological activities in several pharmaceutical areas, including, for example, antitumor. Among this chemical family, indolinone displays very promising antitumor properties by inhibiting various kinase families. These small molecules have a low molecular weight and most of them bind to protein kinases competing with ATP for the ATP-binding site. This review focuses on the indolinone based drugs approved for the treatment of cancer, drugs under clinical trial and then chemical diversity of various synthetic analogues of indolinone and their metabolites as various kinase inhibitors. This review also focused on structural activity relationship (SAR), mechanisms of action and biological targets through which indolinone and its derivatives display their antitumor activity.

show abstract

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

Cited by 52 publications

References 50 publications

Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma

Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma

Critical Role of IRF-8 in Negative Regulation of TLR3 Expression by Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-2 Activity in Human Myeloid Dendritic Cells

Indolinones as Promising Scaffold as Kinase Inhibitors: A Review

Contact Info

Product

Resources

About