Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes

Activation of various interacting stress kinases, particularly the c-Jun N-terminal kinases (JNK), and a concomitant phosphorylation of insulin receptor substrate 1 (IRS-1) at serine 307 play a central role both in insulin resistance and in beta-cell dysfunction. IRS-1 phosphorylation is stimulated by elevated free fatty acid levels through different pathways in obesity. A series of novel pyrido[2,3-d]pyrimidin-7-one derivatives were synthesized as potential antidiabetic agents, preventing IRS-1 phosphorylation at serine 307 in a cellular model of lipotoxicity and type 2 diabetes. (C) 2015 Elsevier Ltd. All rights reserved

Targeting vascular endothelial growth factor receptor 2 and protein kinase d1 related pathways by a multiple kinase inhibitor in angiogenesis and inflammation related processes in vitro.

Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2) and protein kinase D1 (PKD1) signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific inhibitors would be of great value. To test this possibility, we screened our molecular library using recombinant kinase assays and identified the previously described compound VCC251801 with strong inhibitory effect on both VEGFR2 and PKD1. We further analyzed the effect of VCC251801 in the endothelium-derived EA.hy926 cell line and in different inflammatory cell types. In EA.hy926 cells, VCC251801 potently inhibited the intracellular activation and signaling of VEGFR2 and PKD1 which inhibition eventually resulted in diminished cell proliferation. In this model, our compound was also an efficient inhibitor of in vitro angiogenesis by interfering with endothelial cell migration and tube formation processes. Our results from functional assays in inflammatory cellular models such as neutrophils and mast cells suggested an anti-inflammatory effect of VCC251801. The neutrophil study showed that VCC251801 specifically blocked the immobilized immune-complex and the adhesion dependent TNF-alpha -fibrinogen stimulated neutrophil activation. Furthermore, similar results were found in mast cell degranulation assay where VCC251801 caused significant reduction of mast cell response. In summary, we described a novel function of a multiple kinase inhibitor which strongly inhibits the VEGFR2-PKD1 signaling and might be a novel inhibitor of pathological inflammatory pathways

4-Pyrimidinylamino-benzenesulfonamide derivatives and their use for the inhibition of polo-like kinase 1 (PLK1) for the treatment of cancer and their use for the treatment of bacterial infections

The present invention relates to 4-pyrimidinylamino-benzenesulfonamide derivatives of general formula (I) and pharmaceutically acceptable salts, solvates, hydrates, regioisomeric and polymorphic forms thereof, processes for manufacturing of them, the use of them, as well as pharmaceutical compositions containing at least one of them as pharmaceutically active agent(s) together with pharmaceutically acceptable carrier, excipient and/or diluents, especially for the inhibition of polo-like kinases (PLKs) and the treatment of cancer. Said 4-pyrimidinylamino-benzenesulfonamide compounds have been also identified as new drug candidates for the prevention and/or treatment of infectious diseases like bacterial diseases e.g. tuberculosis, including the currently multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) as well as for preventing tuberculosis

Benzothiophene, benzyloxybenzylidene and indoline derivatives useful for the treatment of tuberculosis

The present invention relates to benzothiophene, benzyloxybenzylidene and indoline-2-one derivatives and the use of said derivatives in the treatment and/or prevention of tuberculosis

Cellular targets of gefitinib

Targeted inhibition of protein kinases with small molecule drugs has evolved into a viable approach for anticancer therapy. However, the true selectivity of these therapeutic agents has remained unclear. Here, we used a proteomic method to profile the cellular targets of the clinical epidermal growth factor receptor kinase inhibitor gefitinib. Our data suggest alternative cellular modes of action for gefitinib and provide rationales for the development of related drugs

Cellular targets of gefitinib

Targeted inhibition of protein kinases with small molecule drugs has evolved into a viable approach for anticancer therapy. However, the true selectivity of these therapeutic agents has remained unclear. Here, we used a proteomic method to profile the cellular targets of the clinical epidermal growth factor receptor kinase inhibitor gefitinib. Our data suggest alternative cellular modes of action for gefitinib and provide rationales for the development of related drugs

VCC251801 specifically inhibited neutrophil response.

<p>Human neutrophils were pre-treated with VCC251801 for 30 minutes in 37°C at the following concentrations: 0.3 μM, 1 μM, 3 μM, 10 μM. Respiratory burst was induced by immune-complex <b>(A)</b> or 20 ng/ml TNFα on Fibrinogen coating <b>(B)</b>. Every compound was tested at 10 μM using 100 nM PMA stimulation <b>(C)</b>. The dose response curves of VCC251801 and the reference inhibitors are presented using immune complex <b>(D-F)</b> or TNFα on fibrinogen coating <b>(G-I)</b> stimulation. In dose response experiments, each compound was used at the concentrations mentioned above. Every experiment was performed at least 3 times at constant 0.1% DMSO concentration.</p

Treating endothelial cell with VCC251801 did not interfere with cell viability.

<p>The endothelial EA.hy926 cells were incubated with VCC251801 and reference compounds in 0.4–50 μM concentration range for 24 <b>(A)</b> and for 48 <b>(B)</b> hours at constant 0.5% DMSO concentration and cell viability was determined by MTT-assay. <b>(C)</b> Absolute IC₅₀ values from MTT-assays were calculated using non-linear regression from at least three independent experiments.</p