Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis

Arthritis Rheum. 2008 Dec;58(12):3765-75. doi: 10.1002/art.24047.


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.

Conclusion: 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.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism*
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Female
  • Fibroblasts / cytology
  • HSP72 Heat-Shock Proteins / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Jurkat Cells
  • Macrophages / cytology
  • Male
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • NIH 3T3 Cells
  • Neovascularization, Physiologic / physiology
  • Nitric Oxide / metabolism
  • Rats
  • Rats, Inbred Lew
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Signal Transduction / immunology
  • Synovial Membrane / cytology
  • omega-Conotoxins


  • Anti-Inflammatory Agents
  • Benzamides
  • Cytokines
  • HSP72 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • NF-kappa B
  • SNX-7081
  • omega-Conotoxins
  • Nitric Oxide
  • ziconotide
  • Mitogen-Activated Protein Kinases