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.

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.

• Authors: John W Rice, James M Veal, R Patrick Fadden, Amy F Barabasz, Jeffrey M Partridge, Thomas E Barta, Laura G Dubois, Kenneth H Huang, Sarah R Mabbett, Melanie A Silinski, Paul M Steed, Steven E Hall
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 58 Issue 12 Pg. 3765-75 (Dec 2008) ISSN: 0004-3591 [Print] United States
• PMID: 19035474 (Publication Type: Journal Article)

Chemical References

• 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

Topics

• Administration, Oral
• Animals
• Anti-Inflammatory Agents (pharmacokinetics, pharmacology)
• Arthritis, Rheumatoid (drug therapy, immunology, metabolism)
• Benzamides (pharmacokinetics, pharmacology)
• Cytokines (metabolism)
• Disease Models, Animal
• Down-Regulation (drug effects, 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, immunology)
• Synovial Membrane (cytology)
• omega-Conotoxins