Protein kinase C inhibition

Inhibitors specific for PKC-p have a more favorable toxicity profile. In fact, in a study by Aiello et al. (52), the effect of VEGF on retinal vascular permeability appeared to be mediated predominantly by the p-isoform of PKC. There was 95% inhibition of VEGF-induced permeability after administration of a PKC p-isoform-selective inhibitor (50). Studies are currently being conducted with a new PKC-p inhibitor, known as ruboxistaurin mesylate. Thus far, based on animal 

The efficacy of ruboxistaurin mesylate (LY333531) to delay or stop DME progression has been evaluated in a recent trial. This trial, the PKC-DMES trial was a multicenter, double-masked, placebo-controlled trial that included 686 patients. In this study, when patients with very poor glycemic control (HbAlc 10%) were excluded from the data, ruboxistaurin (32 mg dose) was associated with a reduction in DME progression (52). 

As described above, VEGF enhances vascular permeability and thereby promotes macular edema. Several studies have looked or are currently looking for ways to inhibit VEGF. 

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FERRioLA p c, CODY V and MIDDLETON E (1989) Protein kinase C inhibition by plant... 

Relationship between flavonoid structure and inhibition of phos-phatidylinositol 3-kinase a comparison with tyrosine kinase and protein kinase C inhibition Biochemical Pharmacology 53, 1649-57. 

TASINATO A D, BOISCOBOINIK D, BARTOLI G M, MARONi p and Azzi A (1995) d-a-tocopherol inhibition of vascular smooth muscle cell proliferation occurs at physiological concentrations, correlates with protein kinase C inhibition, and is independent of its ntioydd ait xo eriie% Proceedings National Academy Sciences USA 92, 12190-4. 

This method has been applied in the enantioselective synthesis of d-erythro-sphingosine and phytosphingosine. Sphingosine became an important substance for studying signal transduction since the discovery of protein kinase C inhibition by this compound.48 Many efforts have been made to synthesize sphingosine and its derivatives.49 Kobayashi et al. reported another route to this type of compound in which a Lewis acid-catalyzed asymmetric aldol reaction was a key step. 

Figure 6.15. Structures of some protein kinase C inhibitors. Staurosporine is a potent inhibitor of protein kinase C, but is not selective. Some derivatives of protein kinase C, such as Ro31-8220 and Ro31-8425, retain a potency similar to that of the parent molecule in protein kinase C inhibition, but are much more specific.

Chmura, S. J., Nodzenski, E., Weichselbaum, R. R., and Quintans, J., 1996, Protein kinase C inhibition induces apoptosis and ceramide production through activation of a neutral sphingomyelinase. Cancer Res. 56 2711-2714. 

Figure 7. Multiclass NaTve Bayes modeling within Pipeline Pilot software (www.scitegic.com) based on the WOMBAT chemogenomics dataset Probabilistic target predictions are possible for compounds given only their chemical structure. In the example shown, the WOMBAT targets were predicted for Calphostin C, a known protein kinase C inhibiting natural product Tubulin and beta-hexosaminidase are predicted as additional possible targets.

Protein kinase C inhibition. Hexane extract, at a concentration of 30 (Xg/mL on... 

In the imphosphorylated form and in the absence of Ca, the MARCKS proteins bind to actin filaments and bring about crosshnking of the latter. Binding of Ca Vcal-modulin or phosphorylation by protein kinase C inhibits the crosslinking activity. The MARCKS proteins can thus modulate the aggregation status of actin filaments and function as effectors for the conversion of extracellular signals that are carried into the cell via G-protein-coupled receptors and/or tyrosine kinase receptors. 

Hennings, H., Blumberg, P. M., Pettit, G. R., Herald, C. L., Shores, R., and Yuspa, S. H., Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin, Carcinogenesis, 8, 1343, 1987. 

Hung AY, Haass C, Nitsch RM, et al. Activation of protein kinase C inhibits cellular production of the amyloid b-protein. J Biol Chem 1993 268 22,959-22,962. 

Chida, K., Murakami, A., Tagawa, T., Ikuta, T., and Kuroki, T., Cholesterol sulfate, a second messenger for the n isoform of protein kinase C, inhibits promotional phase in mouse skin carcinogenesis, Cancer Res., 55, 4865, 1995. 

Some selected alkaloids are readily accessible via the corresponding chromium carbenes. A versatile synthesis of indolocarbazoles 133 and 134, bioactive natural products with interesting protein kinase C inhibiting properties, is based on photobenzannulation. Depending on the nature of the Cj-synthon, dioxy and oxyamino derivatives have been synthesized in good to very good yields (Scheme 46) [96]. 

Ricciarelli, R., Maroni, P., Ozer. N., Zingg, J. M., and Azzi, A. (1999) Age-dependent increase of collagenase expression can be reduced by alpha-tocopherol via protein kinase C inhibition. Free Radic Biol Med 11, 729-37. 

Zhu SJ, Kavanaugh MP, Sonders MS, Amara SG, Zahniser NR (1997) Activation of protein kinase C inhibits uptake, currents and binding associated with the human dopamine transporter expressed in Xenopus oocytes. J Pharmacol Exp T/ier 282 1358-1365. 

Pomero F, Allione A, Beltramo E, et al. Effects of protein kinase C inhibition and activation on proliferation and apoptosis of bovine retinal pericytes. Diabetologia 2003 46 416-419. 

Inasmuch as VASP appears to be localized to focal adhesions in intact platelets, the interesting possibility exists that PKG regulates focal adhesion assembly. In a report by Murphy-Ullrich and coworkers (1994), selective inhibitors of PKG, but not PKA or protein kinase C, inhibited thrombospondin-evoked focal adhesion disassembly, suggesting that PKG mediates thrombospondin action. This would be a new role for PKG in regulating cellular shape and motility. The role of VASP in this process is currently unknown, but the availability of cDNA probes for controlling expression of this unique protein may provide answers. 

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