AG 99

AG 99 is a potent inhibitor of EGF receptor tyrosine kinase with IC50 value of 10 μM [1].

The epidermal growth factor receptor (EGFR) is the cell-surface receptor for epidermal growth factor and plays an important role in tumor invasion and cancer cell proliferation.

AG 99 is a potent and competitive EGFR tyrosine kinase inhibitor against both the substrate polyGAT and ATP [1]. In serum-starved human bladder carcinoma cell line 5637 cells, the 145-kDa protein, which was the β-subunit of c-Met/hepatocyte growth factor (HGF) receptor, was phosphorylated on 1003, 1234 and 1235 tyrosine residues. Also, tyrosine kinases EGFR and Src were activated. While, AG99 or inhibitors of Src (PP2, SU6656) significantly inhibited tyrosine phosphorylation of p145met and induced cell death through activation of caspase-like proteases. These results suggested that serum-independent growth of 5637 cells was involved by the tyrosine phosphorylation of p145met mediated by Src and EGFR [2].

References:
[1].  Gazit A, Osherov N, Gilon C, et al. Tyrphostins. 6. Dimeric benzylidenemalononitrile tyrophostins: potent inhibitors of EGF receptor tyrosine kinase in vitro. J Med Chem, 1996, 39(25): 4905-4911.
[2].  Yamamoto N, Mammadova G, Song RX, et al. Tyrosine phosphorylation of p145met mediated by EGFR and Src is required for serum-independent survival of human bladder carcinoma cells. J Cell Sci, 2006, 119(Pt 22): 4623-4633.

Li/Ag ratio dependent structure and upconversion photoluminescence of Li(x)Ag(1-x)Yb(0.99)(MoO4)(2):0.01Er(3+) phosphors.[Pubmed:25557109]

Phys Chem Chem Phys. 2015 Feb 7;17(5):3689-96.

A series of double molybdate scheelite-type phosphors LixAg1-xYb0.99(MoO4)2:0.01Er(3+) (x = 0, 0.1, 0.3, 0.5, 0.7, 0.9, 1.0) were synthesized by the solid state reaction method, and their crystal structures and upconversion (UC) luminescence properties were investigated in detail. The phase structure evolution of this series samples was discussed and the selected Li0.5Ag0.5Yb0.99(MoO4)2:0.01Er(3+) was analyzed based on the Rietveld refinement. The UC emission properties and the related UC mechanism were also studied. With an increasing Li/Ag ratio in this host, the UC emission intensities of LixAg1-xYb0.99(MoO4)2:0.01Er(3+) increased obviously, and the enhancement could be attributed to the coupling effect and the nonradiative transition between two energy levels of LixAg1-xYb(MoO4)2 matrices and the activator Er(3+), which have also been analyzed based on the results of the ultraviolet-visible diffuse reflection spectroscopy (UV-vis DRS) and Raman spectroscopy.

AG 60.99: A promising contrast agent for computed tomography of the liver and spleen.[Pubmed:185647]

Radiology. 1976 Nov;121(2):491.

AG 60.99, an emulsion of poppy-seed oil, is proposed as a promising organ-specific agent for computed tomography (CT) of the liver and spleen. This agent not only opacifies the hepatic parenchyma enough to enhance visualization of the bile ducts but also demonstrates the vascular anatomy with smaller doses than those required for conventional studies.

Tyrosine phosphorylation of p145met mediated by EGFR and Src is required for serum-independent survival of human bladder carcinoma cells.[Pubmed:17062641]

J Cell Sci. 2006 Nov 15;119(Pt 22):4623-33.

Here we address the molecular mechanism of serum-independent survival and growth of human bladder carcinoma cell line 5637. Serum starvation promoted tyrosine phosphorylation of a 145-kDa protein and activation of the tyrosine kinase Src and the receptor for epidermal growth factor (EGFR) over a slow time course (>8 hours). The phosphorylated 145-kDa protein was identified as the beta-subunit of c-Met/hepatocyte growth factor (HGF) receptor, p145(met), in which tyrosine residues 1003, 1234, and 1235 were phosphorylated. Inhibitors of Src (PP2, SU6656) or EGFR (AG99), but not p145(met) (K252a), effectively blocked tyrosine phosphorylation of p145(met) and promoted cell death accompanied by activation of caspase-like proteases. Conditioned medium from the serum-starved 5637 cells or purified EGF readily promoted the activation of Src and EGFR, and tyrosine phosphorylation of p145(met) in normally grown 5637 cells, suggesting that autocrine signaling of EGFR ligands is responsible for signal transduction events in serum-starved cells. Consistent with this idea, a monoclonal antibody against EGFR that would interfere with the ligand binding to EGFR blocked tyrosine phosphorylation events and promoted the caspase activation and cell death in serum-free conditions. Such apoptotic cell death was also induced by pretreatment of cells with a high concentration of HGF that downregulated endogenous p145(met). Nevertheless, Cu2+ ions, competitive inhibitors for HGF-binding to p145(met), did not show any effect on cellular functions in serum-free conditions. These results suggest that the serum-independent growth of 5637 cells involves the transmembrane signaling cascade via EGFR ligand(s) (but not HGF), EGFR, Src and p145(met).

Tyrphostins. 6. Dimeric benzylidenemalononitrile tyrophostins: potent inhibitors of EGF receptor tyrosine kinase in vitro.[Pubmed:8960549]

J Med Chem. 1996 Dec 6;39(25):4905-11.

Benzylidenemalononitrile (BMN) tyrphostins were previously found to be potent inhibitors of EGF receptor (EGFR) tyrosine kinase activity. Since these compounds were found to compete for the substrate and sometimes with the ATP site and since EGFR acts as a dimer, we prepared a series of dimeric tyrphostins. These dimeric tyrphostins were built from two BMN units linked by various spacers and designed to fit the dimeric cross-autophosphorylation signal transduction intermediate of the EGFR tyrosine kinases. Structure-activity relationship of these potent dimeric EGF receptor tyrosine kinase inhibitors is reported.

Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors.[Pubmed:2552117]

J Med Chem. 1989 Oct;32(10):2344-52.

A novel class of low molecular weight protein tyrosine kinase inhibitors is described. These compounds constitute a systematic series of molecules with a progressive increase in affinity toward the substrate site of the EGF receptor kinase domain. These competitive inhibitors also effectively block the EGF-dependent autophosphorylation of the receptor. The potent EGF receptor kinase blockers examined were found to competitively inhibit the homologous insulin receptor kinase at 10(2)-10(3) higher inhibitor concentrations in spite of the significant homology between these protein tyrosine kinases. These results demonstrate the ability to synthesize selective tyrosine kinase inhibitors. The most potent EGF receptor kinase inhibitors also inhibit the EGF-dependent proliferation of A431/clone 15 cells with little or no effect on EGF independent cell growth. These results demonstrate the potential use of protein tyrosine kinase inhibitors as selective antiproliferative agents for proliferative diseases caused by the hyperactivity of protein tyrosine kinases. We have suggested the name "tyrphostins" for this class of antiproliferative compounds which act as protein tyrosine kinase blockers.