Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis.
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.
Rice
John W
JW
Serenex Inc., Durham, North Carolina 27701, USA.
Veal
James M
JM
Fadden
R Patrick
RP
Barabasz
Amy F
AF
Partridge
Jeffrey M
JM
Barta
Thomas E
TE
Dubois
Laura G
LG
Huang
Kenneth H
KH
Mabbett
Sarah R
SR
Silinski
Melanie A
MA
Steed
Paul M
PM
Hall
Steven E
SE
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
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