EX527

表观遗传修饰剂；抑制SIRT1组蛋白去乙酰化酶

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产品号 #73652_C

表观遗传修饰剂；抑制SIRT1组蛋白去乙酰化酶

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总览

EX527是一种细胞渗透性、选择性哺乳动物sirtuin 1（SIRT1；IC₅₀=98 nM）的抑制剂，且对SIRT2和SIRT3有抑制作用，但对其他组蛋白去乙酰化酶（HDAC）无作用（Nayagam et al.）。SIRT1是一种烟酰胺腺嘌呤二核苷酸（NAD）依赖性去乙酰化酶，在能量代谢和炎症中发挥作用。研究表明，EX527通过与NAD+衍生的副产物形成三聚体sirtuin复合物来抑制sirtuin（Gertz M et al.）。

分化
·促进体外神经干细胞和神经祖细胞分化为少突胶质细胞（Rafalski et al.）。

免疫学
·恢复脓毒症小鼠模型低炎症期的微血管反应，并增强全身先天免疫反应（Vachharajani et al.）。

疾病建模
·延缓PKD1基因敲除小鼠模型肾脏囊肿生长（Zhou et al.）。

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Document Type

Product Information Sheet

Product Name

EX527

Catalog #

73654

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All

Language

English

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Safety Data Sheet

Product Name

EX527

Catalog #

73654

Lot #

All

Language

English

文献 (5)

SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. Nayagam VM et al. Journal of biomolecular screening 2006 DEC

Abstract

The nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase SIRT1 has been linked to fatty acid metabolism via suppression of peroxysome proliferator-activated receptor gamma (PPAR-gamma) and to inflammatory processes by deacetylating the transcription factor NF-kappaB. First,modulation of SIRT1 activity affects lipid accumulation in adipocytes,which has an impact on the etiology of a variety of human metabolic diseases such as obesity and insulin-resistant diabetes. Second,activation of SIRT1 suppresses inflammation via regulation of cytokine expression. Using high-throughput screening,the authors identified compounds with SIRT1 activating and inhibiting potential. The biological activity of these SIRT1-modulating compounds was confirmed in cell-based assays using mouse adipocytes,as well as human THP-1 monocytes. SIRT1 activators were found to be potent lipolytic agents,reducing the overall lipid content of fully differentiated NIH L1 adipocytes. In addition,the same compounds have anti-inflammatory properties,as became evident by the reduction of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). In contrast,a SIRT1 inhibitory compound showed a stimulatory activity on the differentiation of adipocytes,a feature often linked to insulin sensitization.

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Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Rafalski VA et al. Nature cell biology 2013 JUN

Abstract

Oligodendrocytes-the myelin-forming cells of the central nervous system-can be regenerated during adulthood. In adults,new oligodendrocytes originate from oligodendrocyte progenitor cells (OPCs),but also from neural stem cells (NSCs). Although several factors supporting oligodendrocyte production have been characterized,the mechanisms underlying the generation of adult oligodendrocytes are largely unknown. Here we show that genetic inactivation of SIRT1,a protein deacetylase implicated in energy metabolism,increases the production of new OPCs in the adult mouse brain,in part by acting in NSCs. New OPCs produced following SIRT1 inactivation differentiate normally,generating fully myelinating oligodendrocytes. Remarkably,SIRT1 inactivation ameliorates remyelination and delays paralysis in mouse models of demyelinating injuries. SIRT1 inactivation leads to the upregulation of genes involved in cell metabolism and growth factor signalling,in particular PDGF receptor α (PDGFRα). Oligodendrocyte expansion following SIRT1 inactivation is mediated at least in part by AKT and p38 MAPK-signalling molecules downstream of PDGFRα. The identification of drug-targetable enzymes that regulate oligodendrocyte regeneration in adults could facilitate the development of therapies for demyelinating injuries and diseases,such as multiple sclerosis.

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Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. Zhou X et al. The Journal of clinical investigation 2013 JUL

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 and is characterized by the development of multiple bilateral renal cysts that replace normal kidney tissue. Here,we used Pkd1 mutant mouse models to demonstrate that the nicotinamide adenine dinucleotide-dependent (NAD-dependent) protein deacetylase sirtuin 1 (SIRT1) is involved in the pathophysiology of ADPKD. SIRT1 was upregulated through c-MYC in embryonic and postnatal Pkd1-mutant mouse renal epithelial cells and tissues and could be induced by TNF-α,which is present in cyst fluid during cyst development. Double conditional knockouts of Pkd1 and Sirt1 demonstrated delayed renal cyst formation in postnatal mouse kidneys compared with mice with single conditional knockout of Pkd1. Furthermore,treatment with a pan-sirtuin inhibitor (nicotinamide) or a SIRT1-specific inhibitor (EX-527) delayed cyst growth in Pkd1 knockout mouse embryonic kidneys,Pkd1 conditional knockout postnatal kidneys,and Pkd1 hypomorphic kidneys. Increased SIRT1 expression in Pkd1 mutant renal epithelial cells regulated cystic epithelial cell proliferation through deacetylation and phosphorylation of Rb and regulated cystic epithelial cell death through deacetylation of p53. This newly identified role of SIRT1 signaling in cystic renal epithelial cells provides the opportunity to develop unique therapeutic strategies for ADPKD.

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更多信息

更多信息
Molecular Weight	248.7 g/mol
物种	人, 其它物种, 大鼠, 小鼠, 非人灵长类
Alternative Names	Selisistat
Cas Number	49843-98-3
Chemical Formula	C₁₃H₁₃ClN₂O
纯度	≥ 98%
Target	HDAC
Pathway	Epigenetic