Methionine amino peptidase (MetAP) 2 is the target of the anti- angiogenic natural product fumagillin and so is believed to play a role in angiogenesis. MetAPs are metalloenzymes which cleave the N- terminal methionine from newly formed polypeptides. This allows essential post-translational modifications, such as myristoylation and acetylation, to take place thus generating fully functional proteins.
Analogues of fumagillin have shown activity in several different disease models, where angiogenesis may be relevant, including
oncology. Semi-synthetic analogues of fumagillin, such as TNP-470, have shown evidence of antitumor activity in the clinic but poor pharmacokinetic properties and neurotoxic effects have limited their development. Nevertheless MetAP2 remains a promising oncology
target and inhibitors with improved properties should have potential as anti-angiogenic agents.
We have screened MetAP2 using our fragment-based screening approach (Pyramid™) and identified multiple low molecular weight fragments, which bind at the active site of MetAP2 in diverse ways. Three of these were optimised to novel hit series using structure- based drug design and their anti-angiogenic properties are described here.
View further details below