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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http://dx.doi.org/10.1016/j.bcp.2010.05.019 | DOI Listing |
Asian J Org Chem
January 2025
Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854, USA.
A one-pot process was developed to synthesize in moderate to high yield a series of 2-substituted indoles and 7-azaindoles starting from 2-iodo--mesylarylamines and terminal alkynes in the presence of CuO in DMF at 90-120 °C. Without isolation of any intermediate, our optimized conditions enabled the introduction of ester, phenyl, hydroxymethyl, hydroxyethyl, -Boc-aminomethyl, and methyl at the 2-postion of indoles and 7-azaindoles. The reaction tolerates a variety of substrates containing halogens, or acid- or base-sensitive functional groups without requiring a Pd catalyst, a ligand, or a base.
View Article and Find Full Text PDFACS Omega
January 2025
Department of Chemistry, Faculty of Science, Hacettepe University, Beytepe, Ankara 06800, Turkey.
The sensitive Bisphenol A (BPA) detection by an electrochemical sensor based on gold nanoparticle-doped molecularly imprinted polymer was successfully improved. This study describes the development of a method for BPA detection in both aqueous solution and real water samples using N-methacroyl-(L)-cysteine methyl ester and N-methacryloyl-(L)-phenylalanine methyl ester coated pencil graphite electrodes modified with AuNPs by differential pulse voltammetry (DPV). Importantly, AuNPs, which increase the electroactivity, were used to increase the surface area of a BPA-imprinted pencil graphite electrode (MIP PGE) sensor.
View Article and Find Full Text PDFFungal Biol
February 2025
Department of Food Science, Aarhus University, Agro Food Park 48, 8200, Aarhus, Denmark. Electronic address:
Although a major share of postharvest losses of apples is due to fungal fruit rots, their timely detection is difficult in commercial bulk-storage rooms. Therefore, a method was developed to identify the volatile markers of fruit naturally infected by Phacidiopycnis washingtonensis, a common storage-rot fungus of Northern Europe, and North and South America. Potato dextrose agar, apple juice agar, and fruit of the apple cultivar 'Nicoter' were inoculated with P.
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January 2025
Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Bingol University, 12000 Bingol, Türkiye.
This paper investigated essential oils (EOs) of the endemic Prangos aricakensis (PA) used as spice and aroma by the Turkish people. Using a Clevenger-type device, EOs were obtained for the first time by hydro-distillation from dried parts of PA (L:leaf, S:stem). The EOs of the PALEO and PASEO were analyzed by GC-MS/MS.
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January 2025
Bioinspired & Biomimetic Inorganic Chemistry Laboratory, Department of Chemistry, National Institute of Technology Calicut, Kozhikode, Kerala, 673601, India.
Direct methane to methanol conversion is a dream reaction in industrial chemistry, which takes inspiration from the biological methanol production catalysed by methane monooxygenase enzymes (MMOs). Over the years, extensive studies have been conducted on this topic by bioengineering the MMOs, and tailoring methods to isolate the MMOs in the active form. Similarly, remarkable achievements have been noted in other methane activation strategies such as the use of heterogeneous catalysts or molecular catalysts.
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