Title:Methionine AminoPeptidase Type-2 Inhibitors Targeting Angiogenesis
Volume: 16
Issue: 13
Author(s): Tedman Ehlers, Scott Furness, Thomas Philip Robinson, Haizhen A. Zhong, David Goldsmith, Jack Aribser and J. Phillip Bowen
Affiliation:
Keywords:
ADME, Angiogenesis, Angiogenic inhibitors, Anti-angiogenic compounds, Cancer, Drug design, Fumagillin, Methionine
aminiopeptidase, MetAP-2, Ovalicin, Pharmacophore, Cancer, TNP-470.
Abstract: Angiogenesis has been identified as a crucial process in the development and spread of cancers. There are
many regulators of angiogenesis which are not yet fully understood. Methionine aminiopeptidase is a metalloenzyme with
two structurally distinct forms in humans, Type-1 (MetAP-1) and Type-2 (MetAP-2). It has been shown that small molecule
inhibitors of MetAP-2 suppress endothelial cell proliferation. The initial discovery by Donald Ingber of MetAP-2 inhibition
as a potential target in angiogenesis began with a fortuitous observation similar to the discovery of penicillin activity
by Sir Alexander Fleming. From a drug design perspective, MetAP-2 is an attractive target. Fumagillin and ovalicin,
known natural products, bind with IC50 values in low nanomolar concentrations. Crystal structures of the bound complexes
provide 3-dimensional coordinates for advanced computational studies. More recent discoveries have shown other
biological activities for MetAP-2 inhibition, which has generated new interests in the design of novel inhibitors. Semisynthetic
fumagillin derivatives such as AGM-1470 (TNP-470) have been shown to have better drug properties, but have
not been very successful in clinical trials. The rationale and development of novel multicyclic analogs of fumagillin are
reviewed.
