4311-88-0 Usage
Description
Necrostatin-1 is a specific inhibitor of the death domain receptor-associated adaptor kinase (RIP1) that effectively inhibits TNF-α-induced necroptosis, a non-apoptotic cell death pathway. It is an ATP-competitive inhibitor with an EC50 of 182 nM for RIP1 and 490 nM for TNF-α-induced necroptosis in 293T cells. Necrostatin-1 has demonstrated protective effects in mouse models of ischemic brain injury and myocardial infarction, as well as reducing glutamate-induced oxytosis in HT-22 cells.
Uses
Used in Pharmaceutical Research:
Necrostatin-1 is used as a research tool for investigating the role of necroptosis in various pathological conditions. Its ability to inhibit RIP1 kinase activity makes it a valuable compound for studying the molecular mechanisms underlying necroptosis and its contribution to disease progression.
Used in Neuroprotection:
Necrostatin-1 is used as a neuroprotective agent in mouse models of ischemic brain injury. Its protective effect highlights its potential in developing therapeutic strategies for treating neurological disorders associated with ischemic damage.
Used in Cardiac Protection:
Necrostatin-1 is used as a cardioprotective agent in various mouse heart models. It inhibits myocardial cell death and reduces infarct size, indicating its potential in the development of treatments for myocardial infarction and other heart-related conditions.
Used in Cellular Biology:
Necrostatin-1 is used as a tool to study the regulation of caspase-independent cell death mechanisms, specifically necroptosis. Its ability to prevent the death of TNF-α-treated FADD-deficient Jurkat cells aids researchers in understanding the molecular pathways involved in necroptosis and its implications in cell survival and death.
Features
A powerful tool for characterizing the role of necroptosis with characterized primary target.
In vitro
Necrostatin-1 (1-100 μM) inhibits the autophosphorylation of overexpressed and endogenous RIP1.It is found RIP1 is the primary cellular target responsible for the antinecroptosis activity of Necrostatin-1. Necrostatin-1 efficiently suppresses necroptotic cell death triggered by an array of stimuli in a variety of cell types. Necrostatin-1, previously identified as small-molecule inhibitor of necroptosis, inhibits RIP kinase-induced necroptosis and inhibits TNF-α-induced necroptosis in jurkat cells with EC50 of 490 nM.
Biological Activity
ATP-competitive death domain receptor-associated adaptor kinase (RIP1) allosteric inhibitor (EC 50 = 182 nM). Blocks non-apoptotic cell death via inhibition of a specific cellular pathway, necroptosis, which leads to necrosis (EC 50 = 494 nM). Reduces ischemic brain injury in a mouse model of stroke.
Biochem/physiol Actions
Necrostatin-1(Nec-1) might exhibit therapeutic benefit against patients with traumatic brain injury (TBI). In addition, it might also be used to treat other acute central nervous system (CNS) disorders that feature necroptosis as a mode of cell death. It is extensively used to study the effect of receptor-interacting protein kinase 1 (RIPK1) on cell death and inflammation in experimental disease models. Nec‐1 protects hippocampal (HT‐22) cells from glutamate‐induced oxytosis via increasing cellular glutathione (GSH) levels, decreasing reactive oxygen species production, inhibiting the nuclear translocation of apoptosis‐inducing factor and B-cell lymphoma 2 (Bcl‐2) /adenovirus E1B 19kDa‐interacting protein 3‐related pathways.
in vitro
previous study indicated that necrostatin-1 was a selective allosteric inhibitor of the death domain receptor–associated adaptor kinase rip1 in vitro. in this study, rip1 was found to be the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. in addition, two other necrostatins, necrostatin-3 and necrostatin-5, were also shown to target the rip1 kinase step in the necroptosis pathway, but through different mechanism compared with that of necrostatin-1. the findings established necrostatins as the first-in-class inhibitors of rip1 kinase, the key upstream kinase involved in the activation of necroptosis [2].
in vivo
a previous study was designed to investigate the protective effects and mechanisms of nec-1 in concanavalin a-induced hepatitis in mice. it was found that in nec-1-treated mice the amelioration in liver functions and histopathological changes and the suppression of inflammatory cytokine production were observed. western blotting analyses showed that the expression of tnf-α, ifn-γ, il2, il6, and rip1 was significantly reduced in the nec-1-treated mice, which was further confirmed by immunofluorescence and immunohistochemistry. in addition, autophagosome formation was significantly reduced by nec-1 treatment. these results indicated that nec-1 could prevent concanavalin a -induced liver injury via rip1-related and autophagy-related pathways [3].
IC 50
necrostatin-1 (nec-1), (r)-5-([7-chloro-1h-indol-3-yl]methyl)-3-methylimidazolidine-2,4-dione (nec-1a) (figure 1a) (degterev et al., 2008), exhibited an inhibitory constant (ic50) of 0.32 mm for rip1 [1].
References
1) Degterev, et al. (2005), Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury‘ Nature Chem. Biol., 1 112
2) Degterev et al. (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins; Nature Chem. Biol., 4 313
3) Smith et.al. (2007), Necrostatin: a potentially novel cardioprotective agent?; Cardiovasc. Drugs Ther., 21 227
4) Xu et.al. (2007), Necrostatin-1 protects against glutamate-induced glutathione depletion and caspase-independent cell death in HT-22 cells; J. Neurochem., 103 2004
Check Digit Verification of cas no
The CAS Registry Mumber 4311-88-0 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 4,3,1 and 1 respectively; the second part has 2 digits, 8 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 4311-88:
(6*4)+(5*3)+(4*1)+(3*1)+(2*8)+(1*8)=70
70 % 10 = 0
So 4311-88-0 is a valid CAS Registry Number.
InChI:InChI=1/C13H13N3OS/c1-16-12(17)11(15-13(16)18)6-8-7-14-10-5-3-2-4-9(8)10/h2-5,7,11,14H,6H2,1H3,(H,15,18)
4311-88-0Relevant articles and documents
Inhibitors of cellular necrosis
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Page/Page column 31, (2008/06/13)
The present invention relates to compounds and pharmaceutical preparations and their use in therapy for preventing or treating trauma, ischemia, stroke and degenerative diseases associated with cell death. Methods and compositions of the invention are particularly useful for treating neurological disorders associated with cellular necrosis.
