A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis.
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.
Bernier
Sylvie G
SG
Department of Preclinical Research, Praecis Pharmaceuticals, Incorporated, 830 Winter Street, Waltham, MA 02451, USA.
Lazarus
Douglas D
DD
Clark
Edward
E
Doyle
Beth
B
Labenski
Matthew T
MT
Thompson
Charles D
CD
Westlin
William F
WF
Hannig
Gerhard
G
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003510:Cyclohexanes; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D012717:Sesquiterpenes; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D018501:Antirheumatic Agents; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005231:Fatty Acids, Unsaturated; C488724:PPI 2458; D018809:Proliferating Cell Nuclear Antigen; D012717:Sesquiterpenes; C026211:fumagillin; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; D014633:Valine