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Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Methionine AminoPeptidase Type-2 Inhibitors Targeting Angiogenesis

Author(s): Tedman Ehlers, Scott Furness, Thomas Philip Robinson, Haizhen A. Zhong, David Goldsmith, Jack Aribser and J. Phillip Bowen

Volume 16 , Issue 13 , 2016

Page: [1478 - 1488] Pages: 11

DOI: 10.2174/1568026615666150915121204

Price: $65

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.

Keywords: ADME, Angiogenesis, Angiogenic inhibitors, Anti-angiogenic compounds, Cancer, Drug design, Fumagillin, Methionine aminiopeptidase, MetAP-2, Ovalicin, Pharmacophore, Cancer, TNP-470.

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