Structure–activity relationship study of novel necroptosis inhibitors

Teng, Xin; Degterev, Alexei; Jagtap, Prakash G.; Xing, Xiaofei; Choi, Sung‐Woon; Denu, Régine; Yuan, Junying; Cuny, Gregory D.

doi:10.1016/j.bmcl.2005.07.077

Cited by 199 publications

(168 citation statements)

References 34 publications

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“…25 This newly discovered death pathway had been named 'necroptosis' and its existence proved with a specific and potent inhibitor of DR-stimulated cell death (necrostatin-1) without caspase signaling. 25,46 Consistently, the appearance of necrotic morphology was completely inhibited. Moreover, it has been reported that necroptosis could additionally induce autophagy as a downstream consequence, however, oneself not being dependent on autophagy.…”

Section: Discussionmentioning

confidence: 58%

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The antibacterial substance taurolidine exhibits anti-neoplastic action based on a mixed type of programmed cell death

Stendel¹,

Biefer²,

Dékány³

et al. 2009

Autophagy

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The antibacterial amino-acid derivative taurolidine (TAU) has been recently shown to exhibit anti-neoplastic activity based on a mechanism, which is still unknown in detail. Cytotoxicity and clonogenic assays were performed and the impact of apoptosis modulators, a radical scavenger, autophagy inhibitors, silencing of apoptosis inducing actor (AIF) and cytochrome-c (Cyt-C) by siRNA, and knockdown of autophagy related genes were evaluated in vitro. The intracellular ATP-content, release of AIF and Cyt-C, and DNA-laddering were investigated. This study could demonstrate cell killing, inhibition of proliferation, and inhibition or prevention of colony formation in human glioma cell lines and ex vivo glioblastoma cells after incubation with TAU. This effect is based on the induction of a mixed type of programmed cell death with the main preference of autophagy, and involvement of senescence, necroptosis and necrosis. This mechanism of action may open a new approach for therapeutic intervention.

show abstract

Section: Discussionmentioning

confidence: 58%

“…5E). Necrostatin-1 at a concentration of 5 μM was able to reduce cell killing induced by 50 μg/ml TAU by 46.2% in U-373 and by 58.9% in LN229 cells, suggesting an involvement of necroptosis at a variable degree in TAU-induced cell killing (Fig. 5E).…”

Section: Research Papermentioning

confidence: 91%

The antibacterial substance taurolidine exhibits anti-neoplastic action based on a mixed type of programmed cell death

Stendel¹,

Biefer²,

Dékány³

et al. 2009

Autophagy

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“…Interestingly, it is inhibited by a family of substituted indoles called necrostatins . Substituents (methyl, halogen) at position 7 on necrostatin result in increased inhibitory activity (Teng et al, 2005). Given their partial structure similarity, it is tempting to speculate that necrostatins and 7BIO might share a target which they affect in opposite directions.…”

Section: Discussionmentioning

confidence: 99%

7-Bromoindirubin-3′-oxime induces caspase-independent cell death

Ribas

Bettayeb²,

Ferandin³

et al. 2006

Oncogene

101

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“…Since the original publication, additional data regarding the properties of Nec-1 have been reported, including off-target activity and metabolic stability in mice, that are important in designing in vitro and, especially, in vivo experiments with Nec-1.Teng et al 2 reported an optimized derivative of Nec-1, termed 7-Cl-O-Nec-1 (66 in ref.2), that was used in ref. 1 to demonstrate the protection in an ischemic brain injury model.…”

mentioning

confidence: 99%

“…Teng et al 2 reported an optimized derivative of Nec-1, termed 7-Cl-O-Nec-1 (66 in ref. 2), that was used in ref.…”

mentioning

confidence: 99%

Addendum: Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury

Degterev¹,

Huang²,

Boyce³

et al. 2013

Nat Chem Biol

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In this Article 1 , we described a small-molecule inhibitor of necroptosis, termed Necrostatin-1 (Nec-1). Since the original publication, additional data regarding the properties of Nec-1 have been reported, including off-target activity and metabolic stability in mice, that are important in designing in vitro and, especially, in vivo experiments with Nec-1.Teng et al. 2 reported an optimized derivative of Nec-1, termed 7-Cl-O-Nec-1 (66 in ref.2), that was used in ref. 1 to demonstrate the protection in an ischemic brain injury model. This molecule showed higher activity in inhibiting necroptosis in Jurkat cells than Nec-1 (EC 50 = 210 nM versus EC 50 = 490 nM), no nonspecific cytotoxicity at high concentrations (~100 mM) and reasonable pharmacokinetic characteristics following intravenous administration in mice. Degterev et al. 3 subsequently reported that Nec-1 shows limited metabolic stability, which is substantially improved with 7-Cl-O-Nec-1. Takahashi et al. 4 also reported that Nec-1 showed paradoxical toxicity at lower, but not higher, doses in a mouse model of systemic inflammatory stress syndrome (SIRS). No such toxicity was observed with 7-Cl-O-Nec-1. Thus, for in-cell and in vivo experiments, we recommend the use of 7-Cl-O-Nec-1.Muller et al. 5 reported that Nec-1, also known by its chemical name of methylthiohydantoin-tryptophan, is a micromolar inhibitor of indolamine 2,3-deoxygenase (IDO) with EC 50 = 11.4 mM in a cell-based assay. Thus, given the ~20-fold higher activity of Nec-1 in a necroptotic assay, the use of lower concentrations of this molecule could be helpful in distinguishing between inhibition of necroptosis and IDOrelated processes. Another known inhibitor of IDO, 1-methyl-dl-tryptophan, lacks activity against necroptosis as reported by both Degterev et al. 3 and Takahashi et al. 4 Notably, both reports show that optimized 7-Cl-O-Nec-1 lacks activity against IDO. Overall, potential nonspecific toxicity, inhibition of IDO and limited stability of Nec-1 should be taken into account when the molecule is used in vivo, whereas 7-Cl-ONec-1 lacks these liabilities and thus represents a superior choice for in vivo studies.

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Structure–activity relationship study of novel necroptosis inhibitors

Cited by 199 publications

References 34 publications

The antibacterial substance taurolidine exhibits anti-neoplastic action based on a mixed type of programmed cell death

The antibacterial substance taurolidine exhibits anti-neoplastic action based on a mixed type of programmed cell death

7-Bromoindirubin-3′-oxime induces caspase-independent cell death

Addendum: Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury

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