Rice John W, Veal James M, Fadden R Patrick, Barabasz Amy F, Partridge Jeffrey M, Barta Thomas E, Dubois Laura G, Huang Kenneth H, Mabbett Sarah R, Silinski Melanie A, Steed Paul M, Hall Steven E
Serenex Inc., Durham, North Carolina 27701, USA.
Arthritis Rheum. 2008 Dec;58(12):3765-75. doi: 10.1002/art.24047.
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).
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.
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.
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.
评估新型小分子热休克蛋白90（Hsp90）抑制剂SNX-7081阻断炎症相关成分的能力，包括细胞因子产生、蛋白激酶活性和血管生成信号传导。在类风湿关节炎（RA）的临床前体内模型中对一种密切类似物进行了评估。
在Jurkat细胞和RA滑膜成纤维细胞（RASF）中对SNX-7081与Hsp90的结合进行了表征。在细胞系统中，使用脂多糖（LPS）、肿瘤坏死因子α或白细胞介素-1β刺激来评估NF-κB核转位的抑制情况。研究了SNX-7081对THP-1细胞、人脐静脉内皮细胞和RASF中细胞因子产生的抑制作用。评估了生长因子刺激后SNX-7081对丝裂原活化蛋白激酶（MAPK）信号级联的破坏作用。在2种相关的血管生成试验中对SNX-7081进行了测试：血小板衍生生长因子对成纤维细胞的激活以及LPS诱导J774巨噬细胞释放一氧化氮（NO）。口服给药后，在大鼠胶原诱导性关节炎和佐剂诱导性关节炎模型中对一种密切类似物SNX-4414进行了评估。
SNX-7081对Hsp90表现出强结合亲和力，并能诱导产生预期的热休克蛋白70（Hsp70）。SNX-7081在纳摩尔浓度下即可阻断NF-κB核转位，并能有效抑制细胞因子产生。SNX-7081显著降低了生长因子对细胞外信号调节激酶（ERK）和应激活化蛋白激酶（JNK）信号的激活作用。NO的产生也被大幅抑制。在动物模型中，SNX-4414完全抑制了 paw肿胀并改善了体重。炎症、血管翳形成、软骨损伤和骨吸收的评分恢复正常。
目前的结果表明，小分子Hsp90抑制剂可影响炎症疾病进程。在SNX-4414中观察到的强大体内疗效为考虑将Hsp90抑制剂用于RA治疗提供了临床前验证。
