产品号 #100-0263_C
烟酰胺磷酸核糖基转移酶抑制剂
总览
FK-866是一种高度特异性的非竞争性烟酰胺磷酸核糖基转移酶（NAMPT）抑制剂，一种能够调节天然前体烟酰胺NAD+生物合成的酶(Cameron等人；Hasmann和Schemainda)。在肝癌细胞中，FK-866可激活腺苷酸活化蛋白激酶（AMPK）并下调哺乳动物雷帕霉素靶蛋白（mTOR）信号（Schuster等人）。
代谢研究
·FK-866可用于消耗NAD+，NAD+是一种重要的代谢辅助因子(Cameron等人；Hasmann 和 Schemainda；Jadeja等人)。
肿瘤研究
·在HepG2人肝癌细胞中，FK-866可消耗NAD+并通过凋亡诱导延迟细胞死亡(IC₅₀= ~1 nM；Hasmann 和 Schemainda)。在 HepG2 人肝癌细胞中，FK-866 可消耗 NAD+ 并通过凋亡诱导延迟细胞死亡 (IC₅₀ = ~1 nM；Hasmann 和 Schemainda)。
·在多发性骨髓瘤细胞中引发剂量依赖性细胞毒性（Cea等人）。
·诱导神经母细胞瘤SH-SY5Y细胞自噬死亡(IC₅₀= 0.93 nM；Billington等人)。
别名
K 22.175
研究领域
自噬，癌症，代谢
CAS 编号
658084-64-1
化学式
C₂₄H₂₉N₃O₂
分子量
391.5 克/摩尔
纯度
≥98%
通路
mTOR
靶点
AMPK
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Resources and Publications
Publications (6)
Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species-mediated DNA damage. Nature immunology 2019
Abstract
The adoption of Warburg metabolism is critical for the activation of macrophages in response to lipopolysaccharide. Macrophages stimulated with lipopolysaccharide increase their expression of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ salvage, and loss of NAMPT activity alters their inflammatory potential. However, the events that lead to the cells' becoming dependent on NAD+ salvage remain poorly defined. We found that depletion of NAD+ and increased expression of NAMPT occurred rapidly after inflammatory activation and coincided with DNA damage caused by reactive oxygen species (ROS). ROS produced by complex III of the mitochondrial electron-transport chain were required for macrophage activation. DNA damage was associated with activation of poly(ADP-ribose) polymerase, which led to consumption of NAD+. In this setting, increased NAMPT expression allowed the maintenance of NAD+ pools sufficient for glyceraldehyde-3-phosphate dehydrogenase activity and Warburg metabolism. Our findings provide an integrated explanation for the dependence of inflammatory macrophages on the NAD+ salvage pathway.
Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence. Aging 2018 jun
Abstract
Retinal pigment epithelium (RPE) performs numerous functions critical to retinal health and visual function. RPE senescence is a hallmark of aging and degenerative retinal disease development. Here, we evaluated the temporal expression of key nicotinamide adenine dinucleotide (NAD+)-biosynthetic genes and associated levels of NAD+, a principal regulator of energy metabolism and cellular fate, in mouse RPE. NAD+ levels declined with age and correlated directly with decreased nicotinamide phosphoribosyltransferase (NAMPT) expression, increased expression of senescence markers (p16INK4a, p21Waf/Cip1, ApoJ, CTGF and $\beta$-galactosidase) and significant reductions in SIRT1 expression and activity. We simulated in vitro the age-dependent decline in NAD+ and the related increase in RPE senescence in human (ARPE-19) and mouse primary RPE using the NAMPT inhibitor FK866 and demonstrated the positive impact of NAD+-enhancing therapies on RPE cell viability. This, we confirmed in vivo in the RPE of mice injected sub-retinally with FK866 in the presence or absence of nicotinamide mononucleotide. Our data confirm the importance of NAD+ to RPE cell biology normally and in aging and demonstrate the potential utility of therapies targeting NAMPT and NAD+ biosynthesis to prevent or alleviate consequences of RPE senescence in aging and/or degenerative retinal diseases in which RPE dysfunction is a crucial element.
FK866-induced NAMPT inhibition activates AMPK and downregulates mTOR signaling in hepatocarcinoma cells. Biochemical and biophysical research communications 2015 mar
Abstract
BACKGROUND Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme of the NAD salvage pathway starting from nicotinamide. Cancer cells have an increased demand for NAD due to their high proliferation and DNA repair rate. Consequently, NAMPT is considered as a putative target for anti-cancer therapies. There is evidence that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) become dysregulated during the development of hepatocellular carcinoma (HCC). Here, we investigated the effects of NAMPT inhibition by its specific inhibitor FK866 on the viability of hepatocarcinoma cells and analyzed the effects of FK866 on the nutrient sensor AMPK and mTOR complex1 (mTORC1) signaling. RESULTS FK866 markedly decreased NAMPT activity and NAD content in hepatocarcinoma cells (Huh7 cells, Hep3B cells) and led to delayed ATP reduction which was associated with increased cell death. These effects could be abrogated by administration of nicotinamide mononucleotide (NMN), the enzyme product of NAMPT. Our results demonstrated a dysregulation of the AMPK/mTOR pathway in hepatocarcinoma cells compared to non-cancerous hepatocytes with a higher expression of mTOR and a lower AMPK$\alpha$ activation in hepatocarcinoma cells. We found that NAMPT inhibition by FK866 significantly activated AMPK$\alpha$ and inhibited the activation of mTOR and its downstream targets p70S6 kinase and 4E-BP1 in hepatocarcinoma cells. Non-cancerous hepatocytes were less sensitive to FK866 and did not show changes in AMPK/mTOR signaling after FK866 treatment. CONCLUSION Taken together, these findings reveal an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of hepatocarcinoma cells and suggest NAMPT inhibition as a potential treatment option for HCC.
更多信息
| Molecular Weight | 391.5 g/mol |
|---|---|
| Alternative Names | K 22.175 |
| Cas Number | 658084-64-1 |
| Chemical Formula | C₂₄H₂₉N₃O₂ |
| Purity | ≥ 98% |
| Target | AMPK |
| Pathway | mTOR |
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