Small-molecule inhibitor: fumagillin

Name

History: Fumagillin is a product of a fungus, a strain of Aspergillus. The anti-angiogenic activity of fumagillin and some derivatives was described by Ingber et al. (1990), and Sin et al. (1997) showed that fumagillin reacts with methionyl aminopeptidase 2.
Peptidases inhibited: Specifically inhibits methionyl aminopeptidase 2 (MetAP2); the homologous methionyl aminopeptidase 1 (MetAP1: M24.001) is not inhibited (Liu et al., 1998).
Mechanism: Inhibition is irreversible. A crystal structure of a complex between MetAP2 and fumagillin shows that the epoxide group on the ring of the inhibitor reacts covalently with the catalytic His231 (numbered as His79 in the peptidase unit, in MEROPS) (Liu et al., 1998). A single amino acid residue is reported to be responsible for the difference in sensitivity between MetAP1 and MetAP2 (Brdlik & Crews, 2004); this residue, numbered 202 in the MEROPS alignment for subfamily M24A, is alanine in MetAP2, but threonine in MetAP1.
Pharmaceutical relevance: The analogue TPN-470 has been entered into clinical trials for the treatment of various forms of cancer (Kruger & Figg, 2000).
DrugBank: DB02640

CID at PubChem: 5351474
ChEBI: 48635
Structure
Chemical/biochemical name: (2Z,4E,6E,8E)-10-[[5-methoxy-4-[2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl]oxy]-10-oxodeca-2,4,6,8-tetraenoic acid
Formula weight: 459
Related inhibitors: AGM-1470; ovalicin (Griffith et al., 1997); CKD-731 (Han et al., 2000); fumagalone (Zhou et al., 2003); cis-fumagillin (Kwon et al., 2000); 6-oxo-6-deoxyfumagillol (RK-805) (Asami et al., 2004); TNP-470 (Sin et al., 1997).

Comment: Kim et al. (2004) have questioned whether the Inhibition of endothelial cell growth by fumagillin is due to its inhibition of MetAP2.