Abstract
Methionine aminopeptidases (MetAPs), which remove methionine residue from newly synthesized polypeptide chains, are a class of metalloproteases ubiquitously distributed in both eukaryotes and prokaryotes. MetAP-2 inhibition can induce G1 cell cycle arrest, cytostasis in tumor cells in vitro and inhibition of tumor growth in vivo. The discovery of fumagillin with potent antiangiogenic and antiproliferative activities promoted the development of fumagillin analogues as a novel class of anticancer agents. Early drug discovery efforts have focused on analogs of fumagillin, which irreversibly inhibit MetAP-2 through covalent modification of an epoxide. Several fumagillin analogs, like CKD-732, TNP-470 and PPI-2458, were found to be potent selective inhibitors of MetAP-2 (proteolytic activity) and endothelial cell proliferation. Further, they have entered in clinical trials for the treatment of different types of tumors. Recently, attention has been paid to reversible human MetAP-2 inhibitors, such as bengamides, 2-hydroxy-3-aminoamides, anthranilic acid sulfonamides and triazole analogs, which have demonstrated their potential to inhibit angiogenesis and tumor growth in vivo as well. This review article mainly discussed the development of MetAP-2 inhibitors in cancer therapy and also summarized their structure-activity relationships.
Keywords: Angiogenesis inhibitor, antiangiogenesis, endothelial cells, methionine, metastasis, migration, MetAP-2, cancer, MetAP-2 inhibitors, fumagillin, structure-activity relationship, vascular endothelial growth factor
Current Medicinal Chemistry
Title: The Development of MetAP-2 Inhibitors in Cancer Treatment
Volume: 19 Issue: 7
Author(s): S.-Q. Yin, J.-J. Wang, C.-M. Zhang and Z.-P. Liu
Affiliation:
Keywords: Angiogenesis inhibitor, antiangiogenesis, endothelial cells, methionine, metastasis, migration, MetAP-2, cancer, MetAP-2 inhibitors, fumagillin, structure-activity relationship, vascular endothelial growth factor
Abstract: Methionine aminopeptidases (MetAPs), which remove methionine residue from newly synthesized polypeptide chains, are a class of metalloproteases ubiquitously distributed in both eukaryotes and prokaryotes. MetAP-2 inhibition can induce G1 cell cycle arrest, cytostasis in tumor cells in vitro and inhibition of tumor growth in vivo. The discovery of fumagillin with potent antiangiogenic and antiproliferative activities promoted the development of fumagillin analogues as a novel class of anticancer agents. Early drug discovery efforts have focused on analogs of fumagillin, which irreversibly inhibit MetAP-2 through covalent modification of an epoxide. Several fumagillin analogs, like CKD-732, TNP-470 and PPI-2458, were found to be potent selective inhibitors of MetAP-2 (proteolytic activity) and endothelial cell proliferation. Further, they have entered in clinical trials for the treatment of different types of tumors. Recently, attention has been paid to reversible human MetAP-2 inhibitors, such as bengamides, 2-hydroxy-3-aminoamides, anthranilic acid sulfonamides and triazole analogs, which have demonstrated their potential to inhibit angiogenesis and tumor growth in vivo as well. This review article mainly discussed the development of MetAP-2 inhibitors in cancer therapy and also summarized their structure-activity relationships.
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Cite this article as:
Yin S.-Q., Wang J.-J., Zhang C.-M. and Liu Z.-P., The Development of MetAP-2 Inhibitors in Cancer Treatment, Current Medicinal Chemistry 2012; 19 (7) . https://dx.doi.org/10.2174/092986712799320709
DOI https://dx.doi.org/10.2174/092986712799320709 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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