A Methionine Aminopeptidase-2 Inhibitor, PPI-2458, for the Treatment of Rheumatoid Arthritis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-07, Vol.101 (29), p.10768-10773
• Main Authors: Bernier, Sylvie G., Lazarus, Douglas D., Clark, Edward, Doyle, Beth, Labenski, Matthew T., Thompson, Charles D., Westlin, William F., Hannig, Gerhard, Erikson, R. L.
• Format: Article
• Language: English
• Subjects: Aminopeptidases - antagonists & inhibitors; Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Antirheumatic Agents - chemistry; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Arthritis; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - enzymology; Biological Sciences; Cell cycle; Cell Division - physiology; Cell growth; Cells, Cultured; Cyclohexanes; Dosage; Down-Regulation; Drug therapy; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Enzyme inhibition; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Enzymes; Epoxy Compounds - chemistry; Epoxy Compounds - pharmacology; Epoxy Compounds - therapeutic use; Fatty Acids, Unsaturated - chemistry; Human umbilical vein endothelial cells; Humans; Joints; Metalloendopeptidases - antagonists & inhibitors; Proliferating Cell Nuclear Antigen - metabolism; Rats; Rheumatoid arthritis; Secretion; Sesquiterpenes; Synovial Membrane - cytology; Synovial Membrane - drug effects; Synovial Membrane - pathology; Valine - analogs & derivatives; Valine - chemistry; Valine - pharmacology; Valine - therapeutic use; Vehicles
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0404105101

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 ( GI50) 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 ( GI50, 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.