Methionine Aminopeptidase 2 (MetAP-2)

Fumagillin is an anti-angiogenic natural product from Aspergillus fumigatus that served as the structural parent for the anti-tumor drug candidate TNP-470 (AGM1470).  Our lab was the first to show that fumagillin/TNP-470 covalently binds and inhibits the metalloprotease methionine aminopeptidase 2 (MetAP-2).  Our subsequent studies showed that the selective endothelial cytostatic activity of fumagillin/TNP-470 requires p21CIP/Waf for its G1 cell cycle arrest.  In addition, our MetAP-2 knockout mouse validated this protein as a new anti-angiogenic drug target.  More recently, we have shown that MetAP-2 inhibition perturbs the non-canonical Wnt/Planar Cell Polarity (PCP) pathway and that genetic disruption of PCP signaling blocks normal endothelial cell biology.  These results suggest that other small molecule PCP inhibitors could serve new anti-angiogenic drug candidates.

Relevant Publications:

Liu S, Widom J, Kemp CW, Crews CM, Clardy J
Science 1998 282 5392 1324-1327
Sin N, Meng L, Wang MQW, Wen JJ, Bornmann WG, Crews CM
Proc. Natl. Acad. Sci. USA 1997 94 12 6099-6103