METAP2 - Clinical Significance

Clinical Significance

Numerous studies implicate MetAP2 in angiogenesis. Specifically, the covalent binding of either the ovalicin or fumagillin epoxide moiety to the active site histidine residue of MetAP2 has been shown to inactivate the enzyme, thereby inhibiting angiogenesis. The way in which MetAP2 regulates angiogenesis has yet to be established, however, such that further study is required to validate that antiangiogenic activity results directly from MetAP2 inhibition. Nevertheless, with both the growth and metastasis of solid tumors depending heavily on angiogenesis, fumagillin and its analogs—including TNP-470, caplostatin, and beloranib—as well as ovalicin represent potential anticancer agents. Moreover, the ability of MetAP2 to decrease cell viability in prokaryotic and small eukaryotic organisms has made it a target for antibacterial agents. Thus far, both fumagillin and TNP-470 have been shown to possess antimalarial activity both in vitro and in vivo, and fumarranol, another fumagillin analog, represents a promising lead.

Another METAP2 inhibitor beloranib (ZGN-433) has shown efficacy in reducing weight in severely obese subjects. MetAP2 inhibitors work by re-establishing balance to the ways the body metabolizes fat, leading to substantial loss of body weight.