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A Novel Methionine Aminopeptidase-2 Inhibitor, PPI-2458, Inhibits Non–Hodgkin's Lymphoma Cell Proliferation In vitro and In vivo

Authors' Affiliations: ¹ Department of Cell Biology, Repligen; ² Department of Preclinical Research and Analytical Pharmacology, Praecis Pharmaceuticals Incorporated, Waltham, Massachusetts; ³ Department of Toxicology, Memory Pharmaceuticals, Montvale, New Jersey; and ⁴ Department of Drug Metabolism, Merck & Company Incorporated, West Point, Pennsylvania

Requests for reprints: William F. Westlin, Department of Preclinical Research, Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451. Phone: 781-795-4395; E-mail: william.westlin{at}praecis.com.

Purpose: 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.

Experimental Design: 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.

Results: Oral PPI-2458 caused a reduction in germinal center size and number in lymphoid tissues from treated animals. PPI-2458 potently inhibited growth (GI₅₀ = 0.2-1.9 nmol/L) of several NHL lines in a manner that correlated with MetAP-2 inhibition. Moreover, orally administered PPI-2458 significantly inhibited SR tumor growth, which correlated with inhibition of tumor MetAP-2 (>85% at 100 mg/kg) in mice.

Conclusions: These results show the potent antiproliferative activity of PPI-2458 on NHL lines in vitro and oral antitumor activity in vivo and suggest the therapeutic potential of PPI-2458 as a novel agent for treatment of NHL should be evaluated in the clinical setting.

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