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.
Current Topics in Medicinal Chemistry
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.
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Ehlers Tedman, Furness Scott, Robinson Philip Thomas, Zhong A. Haizhen, Goldsmith David, Aribser Jack and Bowen Phillip J., Methionine AminoPeptidase Type-2 Inhibitors Targeting Angiogenesis, Current Topics in Medicinal Chemistry 2016; 16 (13) . https://dx.doi.org/10.2174/1568026615666150915121204
DOI https://dx.doi.org/10.2174/1568026615666150915121204 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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