Correlation of tumor growth suppression and methionine aminopetidase-2 activity blockade using an orally active inhibitor.
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.
Wang
Jieyi
J
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. jieyi.wang@abbott.com
Tucker
Lora A
LA
Stavropoulos
Jason
J
Zhang
Qian
Q
Wang
Yi-Chun
YC
Bukofzer
Gail
G
Niquette
Amanda
A
Meulbroek
Jonathan A
JA
Barnes
David M
DM
Shen
Jianwei
J
Bouska
Jennifer
J
Donawho
Cherrie
C
Sheppard
George S
GS
Bell
Randy L
RL
D000284:Administration, Oral; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D011480:Protease Inhibitors; D011994:Recombinant Proteins; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases