Uses
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].
Enzyme inhibitor
This orally bioavailable, selectively cytotoxic agent (FWfree-acid = 424.54 g/mol; Photosensitive; Store in dark: IUPAC: [(3R,4S,5S,6R)-5-methoxy-4- [(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro2.5]octan- 6-yl] N-[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate), a synthetic analogue of an Aspergillus fumigatus secondary metabolite (See Fumagillin), suppresses the formation of new blood vessels and inhibits endothelial cell proliferation and angiogenesis. Its epoxide group reacts with an active-site histidyl residue in methionyl aminopeptidase type II. Because removal of the N-terminal methionine from many proteins is required for their biologic activity, subcellular localization, and stability, methionyl-aminopeptidase plays a pivotal co-regulatory role in translation. PPI-2458 potently inhibits the proliferation of human fibroblast-like synoviocytes, or HFLS-RA (GI50 = 0.04 nM) derived from RA patients, showing >95% inhibition at 1 nM. Proliferation of human umbilical vein endothelial cells (HUVEC) is similarly inhibited (GI50 = 0.2 nM) by PPI-2458. Moreover, PPI-2458 inhibition of MetAP-2 catalysis (IC50 = 0.2 nM) in HFLS-RA is directly correlated with cell growth inhibition and a decrease in the DNA polymerase processivity factor PCNA. PPP-2458 also protects the a-subunit of eukaryotic initiation factor 2 from inhibitory phosphorylation. Based on the structure of TNP-470, a fumagillin analogue that exhibits dose-limiting CNS toxicity, PPI-2458 was designed to retain antiproliferative activity while improving its CNS toxicity profile. PPI-2458 also inhibits proliferation of B16F10 melanoma cells in vitro, (GI50 = 0.2 nM). This property, coupled with the absence of detectable resistance to PPI-2458 and the induction of morphological features of differentiated melanocytes, commends this agent for melanoma chemotherapy. PPI-2458 also inhibits non-Hodgkin's lymphoma cell proliferation in vitro and in vivo. Metabolic data demonstrate the participation of active metabolites in the in vivo efficacy of PPI-2458.
in vivo
PPI-2458 (0-50 mg/kg, Orally, qod) reverses joint swelling and inflammation in the PG-PS (25 mg/kg, i.p.)-induced arthritis model[1].
PPI-2458 (0-3 mg/kg, Nasogastric intubation, qod) shows a decrease in germinal center lymphocytes in experimentally naive cynomolgus monkeys[2].
PPI-2458 (0-100 mg/kg, Orally, qod) significantly suppresses tumor growth in a dose-dependent manner in severe combined immunodeficient mice with SR tumor xenografts [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. |
References
[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. DOI:10.1073/pnas.0404105101
[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. DOI:10.1158/1078-0432.CCR-05-0871
