Methionine aminopeptidase 2 inhibition: antiangiogenesis and tumour therapy

Abstract

Methionine, used to initiate protein synthesis in eukaryotes, is largely recovered as a co-translational hydrolysis event catalysed by two related enzymes, methionine aminopeptidase (MetAP)1 and 2. One of these, MetAP2, is covalently modified, and thus catalytically inactivated, by a class of drugs related to the fungal polyene antibiotic, fumagillin. This irreversible inhibition results in cell cycle arrest in endothelial cells (as well as a number of other cells) and prevents vascular growth. TNP-470, a member of this group, has been examined in clinical trials. Thus, these and other inhibitors of MetAP2, are a part of the growing class of antiangiogenic drugs with potential for treating cancer and other diseases related to neovascularisation. A large class of non-peptidic reversible inhibitors, as well as antisense and dominant-negative inhibitors, have been developed toward this end.