ArticleBiochemical pharmacology2010
Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112.
Article in Biochemical pharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 41 citations in OpenAlex.
- Targeting SHP2 with an Active Site Inhibitor Blocks Signaling and Breast Cancer Cell Phenotypes.ACS bio & med chem Au · 2023Article
- Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling.Nature communications · 2022Article
- Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies.Acta pharmaceutica Sinica. B · 2021Review
- Novel Small-Molecule Inhibitor for the Oncogenic Tyrosine Phosphatase SHP2 with Anti-Breast Cancer Cell Effects.ACS omega · 2020Article
- A specific amino acid context in EGFR and HER2 phosphorylation sites enables selective binding to the active site of Src homology phosphatase 2 (SHP2).The Journal of biological chemistry · 2020Article
- Phosphotyrosine isosteres: past, present and future.Organic & biomolecular chemistry · 2020Review
- Improving Obesity and Insulin Resistance by Targeting Skeletal Muscle MKP-1.Journal of cellular signaling · 2020Article
- Cytotoxic activity of Shp2 inhibitor fumosorinone in human cancer cells.Oncology letters · 2018Article
- Escape from IFN-γ-dependent immunosurveillance in tumorigenesis.Journal of biomedical science · 2017Review
- Discovery of a Novel Inhibitor of the Protein Tyrosine Phosphatase Shp2.Scientific reports · 2015Article
- Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma.Oncotarget · 2015Article
- Enhanced anti-melanoma efficacy of interferon alfa-2b via inhibition of Shp2.Cancer letters · 2012Article
- Erlotinib inhibits progression to dysplasia in a colitis-associated colon cancer model.World journal of gastroenterology · 2011Article
- Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening.Bioorganic & medicinal chemistry letters · 2011Article
- 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.Journal of immunology (Baltimore, Md. : 1950) · 2011Article
- Shp2 protein tyrosine phosphatase inhibitor activity of estramustine phosphate and its triterpenoid analogs.Bioorganic & medicinal chemistry letters · 2011Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
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 Shp2(E76K) mutant-transformed TF-1 myeloid cells with SPI-112Me resulted in inhibition of Shp2(E76K)-dependent cell survival, which is associated with inhibition of Shp2(E76K) PTP activity, Shp2(E76K)-induced Erk1/2 activation, and Bcl-XL expression. Furthermore, SPI-112Me enhanced interferon-gamma (IFN-gamma)-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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.