The Development of MetAP-2 Inhibitors in Cancer Treatment

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.

Common therapeutic target for both cancer and obesity

“…They include bengamides, 2-hydroxy-3-aminoamides, anthranilic acid sulfonamides and triazole analogs[65-68]. Most of the reversible MetAP2 inhibitors, except the bengamides, have not entered clinical trials because they are not as potent as irreversible[66]. Recently, using the fragment-based drug discovery approach (FBDD), a 6-substituted indazole core was identified as an orally efficacious potent reversible MetAP2 inhibitor[69].…”

Pharmacological Modulation of the N-End Rule Pathway and Its Therapeutic Implications

“…Fumagillin, an antibiotic isolated from a fungus Aspergillus fumigatus fresenius , binds to and irreversibly inactivates MetAP-2 through covalent modification [110]. In mid-1980s, Judah Folkman and his colleagues accidentally found that the proliferation of endothelial cells was inhibited without causing apoptosis when the cells were contaminated with the same fungus.…”

“…This antiangiogenic compound was later determined to be fumagillin [111]. A series of synthetic fumagillin analogs, such as CKD-732, TNP-470 and PPI-2458, were shown to be more potent than fumagillin and entered clinical trials for the treatment of different types of tumors [110]. Recently, the Arg/N-end rule pathway was reported to have an antiapoptotic function via destabilizing various proapoptotic protein fragments [54].…”

Marine-Derived Angiogenesis Inhibitors for Cancer Therapy

“…Several target proteins that are crucial for angiogenesis have been identified, i.e. , vascular endothelial growth factor (VEGFR)-related kinases [2], matrix metalloproteinases (MMPs) [3], methionine aminopeptidase (MetAP) [4], actin, microtubule [5], and histone deacetylases (HDACs) [6]. Using small molecules that inhibit angiogenesis-associated proteins has become a successful strategy for cancer therapy in the clinic [7].…”