title: A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis.
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.
authors.affiliation: Department of Preclinical Research, Praecis Pharmaceuticals, Incorporated, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: Sylvie G
authors.initials: SG
authors.lastname: Bernier
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Lazarus
authors.forename: Edward
authors.initials: E
authors.lastname: Clark
authors.forename: Beth
authors.initials: B
authors.lastname: Doyle
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Labenski
authors.forename: Charles D
authors.initials: CD
authors.lastname: Thompson
authors.forename: William F
authors.initials: WF
authors.lastname: Westlin
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hannig
mesh_terms: 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*
chemical_list: 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