Disease relevance of Graphinone

• Chlovalicin, a ovalicin derivative with a chlorinated methylene moiety at the C-1 position of the cyclohexane ring, dose-dependently inhibited the growth of IL-6 dependent MH60 cells (IC50, 7.5 microM) in the presence of 0.2 U/ml IL-6 and, to a lesser extent, the growth of B16 melanoma cells (IC50, 38 microM) [1].
• Enhanced toxicity of the immunosuppressant ovalicin upon application to the skin [2].
• Fumagillin, ovalicin and their analogues have been demonstrated to have antimicrosporidial activity in vitro and in animal models of microsporidiosis [3].

High impact information on Graphinone

• To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin [4].
• One domain of Protac-1 contains the I kappa B alpha phosphopeptide that is recognized by the F-box protein beta-TRCP, whereas the other domain is composed of ovalicin [4].
• Fumagillin and ovalicin compose a class of structurally related natural products that potently inhibit angiogenesis by blocking endothelial cell proliferation [5].
• Mutation of this residue to alanine resulted in an ovalicin-sensitive MetAP-1 allele, demonstrating that an alanine at this position is critical for inhibition by ovalicin [6].
• Letter: Application of carbon-13 magnetic resonance to isoprenoid biosynthesis. I. Ovalicin [7].

Biological context of Graphinone

• Comparison of the Type I enzyme with the previously reported complex of ovalicin with Type II MetAP shows that the active site of the former is reduced in size and would incur steric clashes with the bound inhibitor [8].
• Among the other three compounds, only ovalicin showed inhibitory activity (IC50, 27 microM) against MH60 cells [1].
• QSAR of the inhibition of angiogenesis by TNP-470 and ovalicin analogues: another example of an allosteric interaction [9].

Anatomical context of Graphinone

• This observation explains the selective effect of ovalicin on lymphocytes observed in vivo [10].
• QSAR have been formulated for variations of TNP-470 and Ovalicin on various cell lines [9].

Associations of Graphinone with other chemical compounds

• Selective inhibition of amino-terminal methionine processing by TNP-470 and ovalicin in endothelial cells [11].
• Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin [12].

Gene context of Graphinone

• Here we report that S100A4 physically interacts with methionine aminopeptidase 2 (MetAP2), the primary target for potent angiogenesis inhibitors, fumagillin and ovalicin [13].
• This Protac consisted of an SCF(beta-TRCP)-binding phosphopeptide derived from IkappaBalpha linked to ovalicin, which covalently binds MetAP-2 [14].

Analytical, diagnostic and therapeutic context of Graphinone

• The purpose of this study was to apply an in vitro drug screening assay for Encephalitozoon intestinalis and Vittaforma corneae and an in vivo athymic mouse model of V. corneae infection to assess the efficacy of TNP-470 (a semisynthetic analogue of fumagillin), ovalicin, and eight ovalicin derivatives [15].
• Synthetic analogues of TNP-470 and ovalicin reveal a common molecular basis for inhibition of angiogenesis and immunosuppression [16].

References