FK866 (APO866) is an inhibitor of nicotinamide phosphoribosyltransferase (NMPRTase). FK866 (APO866) protects against experimental colitis and colitis−associated tumorigenesis by suppression of activated leukocytes particularly macrophages, inflammatory monocytes and T cells. FK866(APO866) also reduced inflammatory responses of lamina propria mononuclear cells (LPMNC) from colonic biopsies of patients with IBD to a comparable extent as dexamethasone [1].
The IC50 of FK866 (APO866) on NAMPT activity is 1.60±0.32 nmol/L [2].. IC50 of FK866 (APO866) on HepG2 cells is 2.21±0.21 nmol/L. FK866 (APO866) treatment strongly reduced NF-κB phosphorylation consequent to LPS treatment. Inhibition of NAMPT by FK866, or inhibition of SIRT by nicotinamide decreased proliferation and triggered death of 293T cells involving the p53 acetylation pathway [3].. FK866 (APO866) potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells [1].
FK866 (APO866) significantly ameliorated all features of DSS-induced colitis in Rag1−mice and effectively suppresses inflammatory innate immune responses in the absence of adaptive immunity. FK866 (APO866) significantly reduced chemokine and cytokine release, many of those which are macrophage/monocyte derived. Remarkably, the observed suppression was in the range or even superior to well-established anti-inflammatory compounds such as dexamethasone and infliximab [1].
References:
[1].Gerner RR, Klepsch V, Macheiner S, Arnhard K, Adolph TE, Grander C, Wieser V, Pfister A, Moser P, Hermann-Kleiter N, Baier G, Oberacher H, Tilg H, Moschen AR. NAD metabolism fuels human and mouse intestinal inflammation. Gut. 2018 Oct;67(10):1813-1823.
[2].Zhang SL, Xu TY, Yang ZL, Han S, Zhao Q, Miao CY. Crystal structure-based comparison of two NAMPT inhibitors. Acta Pharmacol Sin. 2018 Feb;39(2):294-301.
[3].Thakur BK, Dittrich T, Chandra P, Becker A, Lippka Y, Selvakumar D, Klusmann JH, Reinhardt D, Welte K. Inhibition of NAMPT pathway by FK866 activates the function of p53 in HEK293T cells. Biochem Biophys Res Commun. 2012 Aug 3;424(3):371-7.
FK866 (APO866) 是烟酰胺磷酸核糖转移酶 (NMPRTase) 的抑制剂。 FK866 (APO866) 通过抑制活化的白细胞特别是巨噬细胞、炎性单核细胞和 T 细胞来防止实验性结肠炎和结肠炎相关的肿瘤发生。 FK866(APO866) 还可降低 IBD 患者结肠活检组织固有层单核细胞 (LPMNC) 的炎症反应，其程度与地塞米松相当[1]。
FK866 (APO866) 对 NAMPT 活性的 IC50 为 1.60±0.32 nmol/L [2].. FK866 (APO866) 对 HepG2 细胞的 IC50 为 2.21±0.21 nmol/L。 FK866 (APO866) 处理强烈降低 LPS 处理后的 NF-κB 磷酸化。 FK866 对 NAMPT 的抑制或烟酰胺对 SIRT 的抑制减少了涉及 p53 乙酰化途径的 293T 细胞的增殖并触发了其死亡[3]..FK866 (APO866) 有效抑制了 NAMPT 活性，如粘膜减少所证明的NAD，导致包括 PARP1、Sirt6 和 CD38 在内的 NAD 依赖性酶的丰度和活性降低，核因子 kappa B 活化减少，炎症单核细胞、巨噬细胞和活化 T 细胞的细胞浸润减少[1] .
FK866 (APO866) 显着改善 Rag1-/- 小鼠中 DSS 诱导的结肠炎的所有特征，并在缺乏适应性免疫的情况下有效抑制炎症性先天免疫反应。 FK866 (APO866) 显着减少趋化因子和细胞因子的释放，其中许多是巨噬细胞/单核细胞衍生的。值得注意的是，观察到的抑制作用在范围内甚至优于地塞米松和英夫利昔单抗等公认的抗炎化合物 [1]。