This laboratory and others have shown that agents that inhibit the in vitro catalytic activity of
methionine aminopeptidase-2 (MetAP2) are effective in blocking angiogenesis and
tumor growth in preclinical models. However, these prototype MetAP2 inhibitors are clearly not optimized for
therapeutic use in the clinic. We have discovered an orally active class of MetAP2 inhibitors, the
anthranilic acid sulfonamides exemplified by A-800141, which is highly specific for MetAP2. This orally bioavailable inhibitor exhibits an
antiangiogenesis effect and a broad anticancer activity in a variety of
tumor xenografts including
B cell lymphoma,
neuroblastoma, and prostate and colon
carcinomas, either as a single agent or in combination with
cytotoxic agents. We also have developed a
biomarker assay to evaluate in vivo MetAP2 inhibition in circulating mononuclear cells and in
tumors. This
biomarker assay is based on the N-terminal
methionine status of the MetAP2-specific substrate GAPDH in these cells. In cell cultures in vitro, the
sulfonamide MetAP2 inhibitor A-800141 caused the formation of GAPDH variants with an unprocessed N-terminal
methionine. A-800141 blocked
tumor growth and MetAP2 activity in a similar dose-response in mouse models, demonstrating the antitumor effects seen for A-800141 are causally connected to MetAP2 inhibition in vivo. The
sulfonamide MetAP2 inhibitor and GAPDH
biomarker in circulating leukocytes may be used for the development of a
cancer treatment.