title: Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis.
abstract: OBJECTIVE
  To evaluate the ability of SNX-7081, a novel small molecule inhibitor of Hsp90, to block components of inflammation, including cytokine production, protein kinase activity, and angiogenic signaling. A close analog was evaluated in preclinical in vivo models of rheumatoid arthritis (RA).
  
  
  METHODS
  SNX-7081 binding to Hsp90 was characterized in Jurkat cells and RA synovial fibroblasts (RASFs). Inhibition of NF-kappaB nuclear translocation was evaluated in cellular systems, using lipopolysaccharide (LPS), tumor necrosis factor alpha, or interleukin-1beta stimulation. Suppression of cytokine production in THP-1 cells, human umbilical vein endothelial cells, and RASFs was studied. Disruption of MAPK signaling cascades by SNX-7081 following growth factor stimulation was assessed. SNX-7081 was tested in 2 relevant angiogenesis assays: platelet-derived growth factor activation of fibroblasts and LPS-induced nitric oxide (NO) release in J774 macrophages. A close analog, SNX-4414, was evaluated in rat collagen-induced arthritis and adjuvant-induced arthritis, following oral treatment.
  
  
  RESULTS
  SNX-7081 showed strong binding affinity to Hsp90 and expected induction of Hsp70. NF-kappaB nuclear translocation was blocked by SNX-7081 at nanomolar concentrations, and cytokine production was potently inhibited. Growth factor activation of ERK and JNK signaling was significantly reduced by SNX-7081. NO production was also sharply inhibited. In animal models, SNX-4414 fully inhibited paw swelling and improved body weight. Scores for inflammation, pannus formation, cartilage damage, and bone resorption returned to normal.
  
  
  CONCLUSIONS
  The present results demonstrate that a small molecule Hsp90 inhibitor can impact inflammatory disease processes. The strong in vivo efficacy observed with SNX-4414 provides preclinical validation for consideration of Hsp90 inhibitors in the treatment of RA.
authors.affiliation: Serenex Inc., Durham, North Carolina 27701, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Rice
authors.forename: James M
authors.initials: JM
authors.lastname: Veal
authors.forename: R Patrick
authors.initials: RP
authors.lastname: Fadden
authors.forename: Amy F
authors.initials: AF
authors.lastname: Barabasz
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Partridge
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Barta
authors.forename: Laura G
authors.initials: LG
authors.lastname: Dubois
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Huang
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Mabbett
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Silinski
authors.forename: Paul M
authors.initials: PM
authors.lastname: Steed
authors.forename: Steven E
authors.initials: SE
authors.lastname: Hall
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D019169:Jurkat Cells; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013583:Synovial Membrane / Q000166:cytology; D020960:omega-Conotoxins
chemical_list: D000893:Anti-Inflammatory Agents; D001549:Benzamides; D016207:Cytokines; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D016328:NF-kappa B; C535175:SNX-7081; D020960:omega-Conotoxins; D009569:Nitric Oxide; C078452:ziconotide; D020928:Mitogen-Activated Protein Kinases