Methionine aminopeptidase 2 (MetAP2), a member of the dimetallohydrolase family, is a cytosolic metalloenzyme that catalyzes the hydrolytic removal of N-terminal methionine residues from nascent proteins. Importantly, MetAP2 is found in all organisms and is especially important because of its critical role in tissue repair and protein degradation. For over three decades, MetAP2 has been a tentative drug target for the treatment of cancer, obesity, and autoimmune diseases. Furthermore, MetAP2 plays a key role in angiogenesis and the growth of new blood vessels. Thus, the development of MetAP2 inhibitors has been of great interest.
TNP-470 (also known as AGM-1470), a Fumagillin analogue, is a methionine aminopeptidase-2 (MetAP2) inhibitor. TNP-470 has a potent anticancer effect. For example, in two cholangiocarcinoma cell lines, KKU-M213 and KKU-M214, TNP-470 shows anti-proliferative and anti-invasive activities. This compound significantly inhibits growth of both lines in a dose- and time-dependent manner. In addition, TNP-470 decreases the expression of c-MYC, MMP2 and MMP9 in cholangiocarcinoma cell lines. Moreover, TNP-470 inhibits angiogenesis via selective suppression of MetAP2 in endothelial cells. Besides, TNP-470 attenuates weight gain in high-fat diet-induced mice via a reduction in caloric intake and an increase in energy expenditure. Brakenheilm et al demonstrated that TNP-470 slowed weight gain in ob/ob mice when treatment was started in young animals. Importantly, TNP-470 also increases metabolic rate in hypometabolic adult ob/ob mice.
In summary, TNP-470 is a methionine aminopeptidase-2 inhibitor and also an angiogenesis inhibitor, with anticancer and anti-obesity activities.