A novel methionine aminopeptidase-2 inhibitor, PPI-2458, inhibits non-Hodgkin's lymphoma cell proliferation in vitro and in vivo

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Andrew C CooperCharles D Thompson

Abstract

Fumagillin and related compounds have potent antiproliferative activity through inhibition of methionine aminopeptidase-2 (MetAP-2). It has recently been reported that MetAP-2 is highly expressed in germinal center B cells and germinal center-derived non-Hodgkin's lymphomas (NHL), suggesting an important role for MetAP-2 in proliferating B cells. Therefore, we determined the importance of MetAP-2 in normal and transformed germinal center B cells by evaluating the effects of MetAP-2 inhibition on the form and function of germinal centers and germinal center-derived NHL cells. To examine the activity of PPI-2458 on germinal center morphology, spleen sections from cynomolgus monkeys treated with oral PPI-2458 were analyzed. Antiproliferative activity of PPI-2458 was assessed on germinal center-derived NHL lines in culture. A MetAP-2 pharmacodynamic assay was used to determine cellular MetAP-2 inhibition following PPI-2458 treatment. Finally, inhibition of MetAP-2 and proliferation by PPI-2458 was examined in the human SR NHL line in culture and in implanted xenografts. Oral PPI-2458 caused a reduction in germinal center size and number in lymphoid tissues from treated animals. PPI-2458 potently inhibited growth (GI(50) = 0.2-1.9 n...Continue Reading

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Citations

Feb 7, 2008·Proceedings of the National Academy of Sciences of the United States of America·Jieyi WangRandy L Bell
Jan 18, 2008·Journal of Pharmaceutical Sciences·Jose L Mauriz, Javier González-Gallego
Mar 18, 2008·Bioorganic & Medicinal Chemistry Letters·Manas K HaldarSanku Mallik
Jun 21, 2015·Biochemical and Biophysical Research Communications·Takayuki KannoHarutaka Katano
Jun 8, 2017·World Journal of Biological Chemistry·Yie-Hwa Chang
Jan 29, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Christopher C Arico-MuendelKerry F White
Nov 26, 2009·Journal of Medicinal Chemistry·Christopher C Arico-MuendelKerry F White

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