TRAF-STOP inhibitor 6877002 is a selective inhibitor of CD40-TRAF6 interaction (TRAF-STOPs)[1]. Tumor necrosis factor receptor-associated factor 6 (TRAF6) contributes to CD40-mediated activation of NF-κB, stress-activated protein kinases, and possibly other signaling molecules[2]. TRAF-STOP inhibitor 6877002 can be used to treat atherosclerosis[3].
In vitro, TRAF-STOP inhibitor 6877002 (0-20µM) treatment of bone marrow-derived monocytes/macrophages (BMMs) for 5-6 days significantly inhibited CD40L and RANKL-induced differentiation of BMMs into osteoclasts, inhibited NF-κB signaling, and weakened osteoclast bone resorption capacity[4].
In vivo, intraperitoneal injection of TRAF-STOP inhibitor 6877002 (10μM/kg/day) for 6 weeks in apolipoprotein E-deficient (Apoe−/−) mice significantly inhibited atherosclerosis in mice, reduced the size of the necrotic center of plaques, reduced Ly6G+ neutrophils and CD3+ T cells in plaques, and increased collagen and αSMA+ smooth muscle cells[5]. Intraperitoneal injection of TRAF-STOP inhibitor 6877002 (10μM/kg/day) for 6 weeks in diet-induced obese mice significantly reduced the accumulation of CD4+ and CD8+ T cells and macrophages in adipose tissue, reduced hepatic steatosis and improved insulin sensitivity[6].
References:
[1] van Tiel C M, Seijkens T T, Kusters P J, et al. TRAF-STOP-RHDL-Nanoparticles Reduce Atherosclerosis[J]. Arteriosclerosis, Thrombosis, and Vascular Biology, 2017, 37(suppl_1): A224-A224.
[2] Hostager B S. Roles of TRAF6 in CD40 signaling[J]. Immunologic research, 2007, 39: 105-114.
[3] Rouwet E, Lutgens E. 2016 Jeffrey M. Hoeg award lecture: immune checkpoints in atherosclerosis: toward immunotherapy for atheroprotection[J]. Arteriosclerosis, thrombosis, and vascular biology, 2018, 38(8): 1678-1688.
[4] Huang Y, Wu J, Zhan C, et al. TRAF-STOP alleviates osteoclastogenesis in periodontitis[J]. Frontiers in Pharmacology, 2023, 14: 1119847.
[5] Seijkens T T P, van Tiel C M, Kusters P J H, et al. Targeting CD40-induced TRAF6 signaling in macrophages reduces atherosclerosis[J]. Journal of the American College of Cardiology, 2018, 71(5): 527-542.
[6] Chatzigeorgiou A, Seijkens T, Zarzycka B, et al. Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance[J]. Proceedings of the National Academy of Sciences, 2014, 111(7): 2686-2691.
TRAF-STOP inhibitor 6877002是一种抑制CD40-TRAF6相互作用的选择性抑制剂（TRAF-STOPs）[1]。肿瘤坏死因子受体相关因子6（TRAF6）有助于CD40介导的NF-κ B、应激活化蛋白激酶和可能的其他信号分子的活化[2]。TRAF-STOP inhibitor 6877002可用于治疗动脉粥样硬化[3]。
在体外，TRAF-STOP inhibitor 6877002（0-20µM）处理骨髓来源的单核细胞/巨噬细胞（BMMs）5-6天，显著抑制了CD40L和RANKL诱导BMMs分化为破骨细胞，并抑制NF-κB信号传导，减弱了破骨细胞骨吸收能力[4]。
在体内，TRAF-STOP inhibitor 6877002（10μM/kg/day）通过腹膜内注射治疗载脂蛋白E缺陷（Apoe−/−）小鼠6周，显著抑制了小鼠动脉粥样硬化，使斑块坏死中心变小，减少了斑块内Ly6G+中性粒细胞和CD3+T细胞，增加了胶原和αSMA+平滑肌细胞[5]。TRAF-STOP inhibitor 6877002（10μM/kg/day）通过腹膜内注射治疗饮食诱导肥胖的小鼠6周，显著减少了脂肪组织中CD4+和CD8+ T细胞以及巨噬细胞的积累，减少了肝脂肪变性并改善胰岛素敏感性[6]。