The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C.

https://www.jbc.org/content/268/13/9194.full.pdf

Selective inhibition of protein kinase C isozymes by the indolocarbazole Gö 6976.

Incubation of endothelial cells in vitro with high concentrations of glucose activates protein kinase C (PKC) and increases nitric oxide synthase (NOS III) gene expression as well as superoxide production. The underlying mechanisms remain unknown. To address this issue in an in vivo model, diabetes was induced with streptozotocin in rats. Streptozotocin treatment led to endothelial dysfunction and increased vascular superoxide production, as assessed by lucigenin- and coelenterazine-derived chemiluminescence. The bioavailability of vascular nitric oxide (as measured by electron spin resonance) was reduced in diabetic aortas, although expression of endothelial NOS III (mRNA and protein) was markedly increased. NOS inhibition with N:(G)-nitro-L-arginine increased superoxide levels in control vessels but reduced them in diabetic vessels, identifying NOS as a superoxide source. Similarly, we found an activation of the NADPH oxidase and a 7-fold increase in gp91(phox) mRNA in diabetic vessels. In vitro PKC inhibition with chelerythrine reduced vascular superoxide in diabetic vessels, whereas it had no effect on superoxide levels in normal vessels. In vivo PKC inhibition with N:-benzoyl-staurosporine did not affect glucose levels in diabetic rats but prevented NOS III gene upregulation and NOS-mediated superoxide production, thereby restoring vascular nitric oxide bioavailability and endothelial function. The reduction of superoxide in vitro by chelerythrine and the normalization of NOS III gene expression and reduction of superoxide in vivo by N:-benzoyl-staurosporine point to a decisive role of PKC in mediating these phenomena and suggest a therapeutic potential of PKC inhibitors in the prevention or treatment of vascular complications of diabetes mellitus. The full text of this article is available at http://www.circresaha.org.

Mechanisms Underlying Endothelial Dysfunction in Diabetes Mellitus

The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

Inhibitors of histone deacetylase

Substantial evidence exists supporting a direct role for raf kinases in the development and maintenance of certain human malignancies. Here we test the potential of phosphorothioate antisense oligodeoxynucleotides targeted against human C-raf-1 kinase to specifically inhibit C-raf-1 kinase gene expression and tumor progression in cell culture and in vivo, using human tumor xenograft mouse models. Treatment of human tumor cells with appropriate phosphorothioate antisense oligodeoxynucleotides led to specific inhibition of C-raf kinase gene expression in cell culture and in vivo at well-tolerated doses. Moreover, oligodeoxynucleotide treatment resulted in potent antiproliferative effects in cell culture and potent antitumor effects in vivo against a variety of tumor types that were highly consistent with an antisense mechanism of action for these compounds. These studies strongly suggest that antisense inhibitors targeted against C-raf-1 kinase may be of considerable value as antineoplastic agents that display activity against a wide spectrum of tumor types at well-tolerated doses.

Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C- raf kinase

Analogues of staurosporine were synthesized and their ability to inhibit protein kinases was examined. Staurosporine is a potent but non-selective inhibitor of in vitro protein kinase C(PKC) activity (IC50 6.0 nM). The derivative CGP 41 251 had reduced PKC activity with an IC50 of 50 nM but showed a high degree of selectivity when assayed for inhibition of cyclic AMP-dependent protein kinase (IC50 2.4 microM), S6 kinase (IC50 5.0 microM) and tyrosine-kinase-specific activity of epidermal growth factor receptor (IC50 3.0 microM). Staurosporine and CGP 41 251 exerted growth inhibition in the human bladder carcinoma line T-24, human promyelocytic leukemia line HL-60 and bovine corneal endothelial cells at concentrations which correlated well with in vitro PKC inhibition. In addition, both compounds inhibited the release of H2O2 from human monocytes pre-treated with 12-O-tetradecanoyl-phorbol-13-acetate at non-toxic concentrations. In vivo anti-tumor activity was examined in T-24 human bladder carcinoma xenografts in athymic nude mice. Tumor growth inhibition tests revealed significant anti-tumor activity (2p less than 0.001) at 1/10 of the maximum tolerated doses for both compounds. By contrast, a closely related derivative of staurosporine (CGP 42 700) was inactive at concentrations of over 100 microM in all in vitro enzyme and anti-proliferative assays as well as in animal tumor models. Our data suggest an association between PKC inhibition and anti-proliferative and anti-tumor activity.

A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and In vitro anti‐proliferative as well as In vivo anti‐tumor activity

MEYER, T., REGENASS, U., FABBRO, D., ALTERI, E., RÖSEL, J., MÜLLER, M., CARAVATTI , G. and MATTER, A., A derivative of staurosporine (CGP 41:251) shows selectivity for PKC inhibition and i vitro antiproliferative effects as well as in vivoantitumor activity.Int. J. Cancer,43,851–866 (1989) are not considered reliable. The authors wish to retract these data. In addition, thein vivoexperiments described in the article

https://onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0215%2819990517%2981%3A4%3C669%3A%3AAID-IJC26%3E3.0.CO%3B2-F

A derivative of staurosporine (CGP 41:251) shows selectivity for PKC inhibition and in vitro antiproliferative effects as well as in vivo antitumor activity. Int. J. Cancer,43, 851–866 (1989)

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A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and In vitro anti‐proliferative as well as In vivo anti‐tumor activity

A derivative of staurosporine (CGP 41:251) shows selectivity for PKC inhibition and in vitro antiproliferative effects as well as in vivo antitumor activity. Int. J. Cancer,43, 851–866 (1989)