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:

Sundberg TB, Darricarrere N, Cirone P, Li X, McDonald L, Mei X, Westlake CJ, Clusarski DC, Beynon RJ, Crews CM
Chemistry & Biology 2011 18 10 1300-1311
Hines J, Ju R, Dutschman GE, Cheng YC, Crews CM
J Pharmacol Exp Ther 2010 334 3 729-738
Cirone P, Lin S, Griesbach HL, Zhang Y, Slusarski DC, Crews CM
Angiogenesis 2008 11 4 347-360
Zhang Y, Yeh JR, Mara A, Ju R, Hines JF, Cirone P, Griesbach HL, Schneider I, Slusarski DC, Holley SA, Crews CM
Chem Biol. 2006 13 9 1001-1009
Yeh J-R, Ju R, Brdlik CM, Zhang W, Zhang Y, Matyskiela ME, Shotwell JD, Crews CM
Proc Natl Acad Sci USA 2006 103 27 10379-10384