PPI-2458

PPI-2458 is a potent, orally active, selective and irreversible inhibitor of methionine aminopeptidase-2 (MetAP-2). PPI-2458 can be used for arthritis and lymphoma research[1][2].

Research Areas >> Cancer

Signaling Pathways >> Others >> Others

Research Areas >> Inflammation/Immunology

PPI-2458 可有效抑制 HUVEC 增殖，GI50 为0.2 nM，在1 nM 时最大抑制率大于 95%[1]。 PPI-2458 (0-100 nM, 6天)抑制 SU-DHL-16 细胞的增殖和MetAP-2[2]。 Cell Proliferation Assay[2] Cell Line: SU-DHL-16 cells Concentration: 0, 0.01, 0.1, 1, 10, and 100 nM Incubation Time: 6 days Result: Inhibited SU-DHL-16 proliferation in a dose-dependent fashion with maximum inhibition of 60% achieved at the highest concentration (100 nmol/L) and GI50 at 1.9 nmol/L.

PPI-2458 (0-50 mg/kg，口服，隔日一次)逆转 PG-PS (25 mg/kg, i.p) 诱导的关节炎模型中的关节肿胀和炎症[1]。 PPI-2458 (0-3 mg/kg，鼻胃插管，隔日一次)可导致实验初代食蟹猴生发中心生发中心淋巴细胞减少[2]。 PPI-2458 (0-100 mg/kg，口服，隔日一次)以剂量依赖的方式显著抑制肿瘤生长在SR肿瘤异种移植的严重联合免疫缺陷小鼠中[2]。 Animal Model: Female Lewis rats (101–121 g, PG-PS (25 mg/kg, i.p.)-induced arthritis model)[1] Dosage: 0.25, 1, 5, and 50 mg/kg Administration: Orally (po), started at day 15 after the chronic destructive phase of the disease was established and terminated on day 31 Result: Significantly and dose-dependently attenuated the chronic inflammatory response. Markedly attenuated paw swelling in a dose-dependent manner with maximal protection at an orally administered dose of 50 mg/kg at day 31. Animal Model: Forty-two experimentally naive cynomolgus monkeys[2] Dosage: 0.1 mg/kg (three males and three females), 0.3 mg/kg (three males and three females), 1.0 mg/kg (five males and five females), and 3.0 mg/kg (five males and five females) Administration: Nasogastric intubation every other day (QOD) for 13 days (total of seven treatments) Result: Exhibited a marked decrease in germinal center lymphocytes. Animal Model: 60 female Fox Chase severe combined immunodeficient mice (SR lymphoma cells were injected s.c. above the right hind leg)[2] Dosage: 10, 30, or 100 mg/kg Administration: oral gavage, QOD Result: Significantly suppressed tumor growth in a dose-dependent manner. PPI-2458 administered at 100 mg/kg produced the greatest degree of tumor growth inhibition, which was 57% (P < 0.001) at the end of the study.

[1]. Bernier SG, et al. A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10768-73.  

[2]. Cooper AC, et al. A novel methionine aminopeptidase-2 inhibitor, PPI-2458, inhibits non-Hodgkin's lymphoma cell proliferation in vitro and in vivo. Clin Cancer Res. 2006 Apr 15;12(8):2583-90.