Fumagillin class inhibitors of methionine aminopeptidase-2

Abstract

The growth of solid tumors and the formation of metastases are critically dependent on neovascularization. This dependence on neovascularization, however, is not limited to cancer but is also a major contributing factor in the pathology of autoimmune diseases such as rheumatoid arthritis. Hence, antiangiogenic therapy was recognized as a potentially powerful therapeutic approach in the treatment of these devastating diseases. The discovery of fumagillin and its potent antiangiogenic and antiproliferative activities provided the rationale for the development of fumagillin analogues as a novel class of antiproliferative agents. Molecules of the fumagillin class inhibit the enzymatic activity of methionine aminopeptidase-2 (MetAP-2), and this inhibition is the first step required for the selective growth inhibition of cell types that are dependent on MetAP-2 function for growth. Mechanistically, this growth inhibition is characterized by cytostasis and arrest in the late G1 phase of the cell cycle. TNP-470 was the first MetAP-2 inhibitor of the fumagillin class to enter phase I clinical trials in cancer. Despite some encouraging results in several solid tumors in early phase I/II studies, further clinical development of this molecule was halted, primarily due to dose-limiting neurotoxicities and a poor clinical pharmacokinetic profile. More recently, fumagillin analogues specifically designed to improve upon the clinical deficiencies of TNP-470, such as PPI-2458, have advanced into phase I trials in cancer.