METHIONINE AMINOPEPTIDASE (TYPE-2) IS THE COMMON TARGET FOR ANGIOGENESIS INHIBITORS AGM-1470 AND OVALICIN

Background: Angiogenesis, the formation of new blood vessels, is essen tial for tumor growth. The inhibition of angiogenesis is therefore eme rging as a promising therapy for cancer. Two natural products, fumagil lin and ovalicin, were discovered to be potent inhibitors of angiogene sis due to their inhibition of endothelial cell proliferation. An anal og of fumagillin, AGM-1470, is currently undergoing clinical trials fo r the treatment of a variety of cancers. The underlying molecular mech anism of the inhibition of angiogenesis by these natural drugs has rem ained unknown. Results: Both AGM-1470 and ovalicin bind to a common bi functional protein, identified by mass spectrometry as the type 2 meth ionine aminopeptidase (MetAP2). This protein also acts as an inhibitor of eukaryotic initiation factor 2 alpha (eIF-2 alpha) phosphorylation . Both drugs potently inhibit the methionine aminopeptidase activity o f MetAP2 without affecting its ability to block eIF-2 alpha phosphoryl ation. There are two types of methionine aminopeptidase found in eukar yotes, but only the type 2 enzyme is inhibited by the drugs. A series of analogs of fumagillin and ovalicin were synthesized and their poten cy for inhibition of endothelial cell proliferation and inhibition of methionine aminopeptidase activity was determined. A significant corre lation was found between the two activities. Conclusions: The protein MetAP2 is a common molecular target for both AGM-1470 and ovalicin. Th is finding suggests that MetAP2 may play a critical role in the prolif eration of endothelial cells and may serve as a promising target for t he development of new anti-angiogenic drugs.