Tumor suppression by a rationally designed reversible inhibitor of methionine aminopeptidase-2.

Abstract

Methionine aminopeptidase (MetAP)-2 has been suggested as a novel target for cancer therapy because the anticancer agent TNP-470 irreversibly inactivates the catalytic activity of this enzyme. However, the importance of MetAP2 in cell growth and tumor progression was uncertain because previous data were based on the chemically reactive TNP-470. Here we show that a rationally designed reversible MetAP2 inhibitor, A-357300, suppresses tumor growth preclinically without the toxicities observed with TNP-470. We have synthesized this bestatin-type MetAP2 inhibitor with the aid of crystal structures of the enzyme-inhibitor complexes and parallel synthesis. A-357300 induces cytostasis by cell cycle arrest at the G(1) phase selectively in endothelial cells and in a subset of tumor cells, but not in most primary cells of nonendothelial type. A-357300 inhibits angiogenesis both in vitro and in vivo and shows potent antitumor efficacy in carcinoma, sarcoma, and neuroblastoma murine models. These data affirm that MetAP2 plays a pivotal role in cell growth and establish that reversible MetAP2 inhibitors are promising novel cancer therapeutic agents.

• Authors: Jieyi Wang, George S Sheppard, Pingping Lou, Megumi Kawai, Nwe BaMaung, Scott A Erickson, Lora Tucker-Garcia, Chang Park, Jennifer Bouska, Yi-Chun Wang, David Frost, Paul Tapang, Daniel H Albert, Sherry J Morgan, Michael Morowitz, Suzanne Shusterman, John M Maris, Rick Lesniewski, Jack Henkin
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 22 Pg. 7861-9 (Nov 15 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14633714 (Publication Type: Journal Article)

Chemical References

• A357300
• Antineoplastic Agents
• Chlorobenzenes
• Cyclohexanes
• Protease Inhibitors
• Sesquiterpenes
• Aminopeptidases
• methionine aminopeptidase 2
• Metalloendopeptidases
• O-(Chloroacetylcarbamoyl)fumagillol

Topics

• Aminopeptidases (antagonists & inhibitors)
• Animals
• Antineoplastic Agents (chemistry, pharmacology, toxicity)
• Breast Neoplasms (drug therapy, enzymology)
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Chlorobenzenes (chemistry, pharmacology, toxicity)
• Cornea (blood supply)
• Cyclohexanes
• Drug Design
• Endothelium, Vascular (cytology, drug effects, enzymology)
• Female
• Fibrosarcoma (drug therapy, enzymology)
• Humans
• Metalloendopeptidases (antagonists & inhibitors)
• Mice
• Mice, SCID
• Models, Molecular
• Neovascularization, Physiologic (drug effects)
• Neuroblastoma (drug therapy, enzymology)
• O-(Chloroacetylcarbamoyl)fumagillol
• Protease Inhibitors (chemistry, pharmacology, toxicity)
• Sesquiterpenes (chemistry, pharmacology, toxicity)
• Xenograft Model Antitumor Assays