Abstract |
The hallmark of rheumatoid arthritis (RA) is the progressive destruction of articular joints, characterized by invasive synovial hyperplasia and pathological neovascularization. Here we report that PPI-2458, a member of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibits the proliferation of human fibroblast-like synoviocytes (HFLS-RA), derived from RA patients, with a growth inhibitory concentration 50 (GI(50)) of 0.04 nM and a maximum inhibition of >95% at 1 nM. Human umbilical vein endothelial cells (HUVEC) are similarly inhibited in proliferation by PPI-2458 (GI(50), 0.2 nM). We developed a method to measure the level of MetAP-2 enzyme inhibition after exposure to PPI-2458 and demonstrate that growth inhibition of PPI-2458-sensitive HFLS-RA and HUVEC is linked to MetAP-2 enzyme inhibition, in a dose-dependent fashion. The secretion of several inflammatory mediators such as IL-6 and vascular endothelial growth factor from activated HFLS-RA was not inhibited by PPI-2458. The CNS toxicity profile of PPI-2458, determined by the incidence of seizures, is significantly improved over that of the parental compound TNP-470. In the rat model of peptidoglycan- polysaccharide-induced arthritis, PPI-2458 significantly attenuated paw swelling when therapeutically administered after the onset of chronic disease. We suggest that the mechanism of PPI-2458 action, highly selective and potent anti-proliferative activity on HFLS-RA and HUVEC in vitro, a significantly improved CNS toxicity profile, and marked attenuation of chronic disease in the rat peptidoglycan- polysaccharide arthritis model in vivo, positions this compound as a drug for the treatment of RA.
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Authors | Sylvie G Bernier, Douglas D Lazarus, Edward Clark, Beth Doyle, Matthew T Labenski, Charles D Thompson, William F Westlin, Gerhard Hannig |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 101
Issue 29
Pg. 10768-73
(Jul 20 2004)
ISSN: 0027-8424 [Print] United States |
PMID | 15249666
(Publication Type: Journal Article)
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Chemical References |
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Cyclohexanes
- Enzyme Inhibitors
- Epoxy Compounds
- Fatty Acids, Unsaturated
- PPI 2458
- Proliferating Cell Nuclear Antigen
- Sesquiterpenes
- fumagillin
- Aminopeptidases
- methionine aminopeptidase 2
- Metalloendopeptidases
- Valine
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Topics |
- Aminopeptidases
(antagonists & inhibitors)
- Animals
- Anti-Inflammatory Agents
(chemistry, pharmacology, therapeutic use)
- Antirheumatic Agents
(chemistry, pharmacology, therapeutic use)
- Arthritis, Rheumatoid
(drug therapy, enzymology)
- Cell Division
(physiology)
- Cells, Cultured
- Cyclohexanes
- Down-Regulation
- Endothelial Cells
(cytology, drug effects, metabolism)
- Enzyme Inhibitors
(chemistry, pharmacology, therapeutic use)
- Epoxy Compounds
(chemistry, pharmacology, therapeutic use)
- Fatty Acids, Unsaturated
(chemistry)
- Humans
- Metalloendopeptidases
(antagonists & inhibitors)
- Proliferating Cell Nuclear Antigen
(metabolism)
- Rats
- Sesquiterpenes
- Synovial Membrane
(cytology, drug effects, pathology)
- Valine
(analogs & derivatives, chemistry, pharmacology, therapeutic use)
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