Tumor Suppression by a Rationally Designed Reversible Inhibitor of Methionine Aminopeptidase-2

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

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    61 Scopus citations

    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 G1 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.

    Original languageEnglish (US)
    Pages (from-to)7861-7869
    Number of pages9
    JournalCancer Research
    Volume63
    Issue number22
    StatePublished - Nov 15 2003

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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