Small-Molecule Inhibitors of Necroptosis: Current Status and Perspectives

Zhuang, Chunlin; Chen, Fen‐Er

doi:10.1021/acs.jmedchem.9b01317

Cited by 64 publications

(62 citation statements)

References 130 publications

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“…A better estimation of the oligomeric state of the MLKL executioner domain is hampered by the lack of structural information of MLKL inserted into micelles or the plasma membrane. Necroptosis could, in principle, be inhibited either by tackling the pseudokinase domain or the executioner domain of MLKL (7). Currently, two classes of compounds are reported to inhibit MLKL by covalently binding to Cys86 in the short α-helix 4 located on top of the four-helix bundle, which comprises α-helices 1, 2, 3, and 5.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, necroptosis has been associated with several inflammatory diseases, including amyotrophic lateral sclerosis (4), chronic intestinal inflammation (5), and skin inflammation (6). Therefore, all three proteins involved in the canonical necroptosis signaling and execution cascade (RIPK1, RIPK3, and MLKL) are attractive molecular targets for therapeutic small-molecule intervention (7).…”

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confidence: 99%

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Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis

Rübbelke

Fiegen

Bauer

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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As an alternative pathway of controlled cell death, necroptosis can be triggered by tumor necrosis factor via the kinases RIPK1/RIPK3 and the effector protein mixed-lineage kinase domain-like protein (MLKL). Upon activation, MLKL oligomerizes and integrates into the plasma membrane via its executioner domain. Here, we present the X-ray and NMR costructures of the human MLKL executioner domain covalently bound via Cys86 to a xanthine class inhibitor. The structures reveal that the compound stabilizes the interaction between the auto-inhibitory brace helix α6 and the four-helix bundle by stacking to Phe148. An NMR-based functional assay observing the conformation of this helix showed that the F148A mutant is unresponsive to the compound, providing further evidence for the importance of this interaction. Real-time and diffusion NMR studies demonstrate that xanthine derivatives inhibit MLKL oligomerization. Finally, we show that the other well-known MLKL inhibitor Necrosulfonamide, which also covalently modifies Cys86, must employ a different mode of action.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis

Rübbelke

Fiegen

Bauer

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…[66][67][68][69][70] Intriguingly, specific RIPK3 inhibitors such as GSK'840, GSK'843, and GSK'872 at high concentrations, despite their ability to inhibit necroptosis, favour the assembly of RIPK1/FADD/ caspase-8/FLIP L (complex IIb) leading to caspase activation and apoptosis. 71,72 In a rodent model of catalytically inactive RIPK3 D161N, mice could not survive through the embryonic period because of lethal caspase-8-mediated apoptosis. 73 Moreover, it was shown that blocking either RIPK3 or MLKL augmented the rate of apoptotic cell death in L-929 cells.…”

Section: Other Potential Interventions Against Necroptosis and Ripkmentioning

confidence: 99%

“…Recently, other pharmacological agents that interfere with RIPK3 have been identified such as diacerein, ponatinib, sorafenib and phenhydan 66‐70 . Intriguingly, specific RIPK3 inhibitors such as GSK'840, GSK'843, and GSK'872 at high concentrations, despite their ability to inhibit necroptosis, favour the assembly of RIPK1/FADD/caspase‐8/FLIP L (complex IIb) leading to caspase activation and apoptosis 71,72 . In a rodent model of catalytically inactive RIPK3 D161N, mice could not survive through the embryonic period because of lethal caspase‐8‐mediated apoptosis 73 .…”

Section: Introductionmentioning

confidence: 99%

The role of RIPK3‐regulated cell death pathways and necroptosis in the pathogenesis of cardiac ischaemia‐reperfusion injury

2020

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Despite advancements in management of acute myocardial infarction, this disease remains one of the leading causes of death. Timely reestablishment of epicardial coronary blood flow is the cornerstone of therapy; however, substantial amount of damage can occur as a consequence of cardiac ischaemia/reperfusion (I/R) injury. It has been previously proposed that the pathway leading to major cell death, apoptosis, is responsible for cardiac I/R injury. Nevertheless, there is compelling evidence to suggest that necroptosis, a programmed necrosis, contributes remarkably to both myocardial injury and microcirculatory dysfunction following cardiac I/R injury. Receptor‐interacting protein kinase 1 (RIPK1), RIPK3, and mixed‐lineage kinase domain‐like pseudokinase (MLKL) are shown as the major mediators of necroptosis. In addition to the traditional perception that RIPK1/RIPK3/MLKL‐dependent plasma membrane rupture is fundamental to this process, several RIPK3‐related pathways such as endoplasmic reticulum stress and mitochondrial fragmentation have also been implicated in cardiac I/R injury. In this review, reports from both in vitro and in vivo studies regarding the roles of necroptosis and RIPK3‐regulated necrosis in cardiac I/R injury have been collectively summarized and discussed. Furthermore, reports on potential interventions targeting these processes to attenuate cardiac I/R insults to the heart have been presented in this review. Future investigations adding to the knowledge obtained from these previous studies are needed in the pursuit of discovering the most effective pharmacological agent to improve cardiac I/R outcomes.

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“…[9] Following the necrostatins, several inhibitors of necroptosis were subsequently described over the last decade. [10] Representative examples are given in Figure 1. For instance, GSK has disclosed a chemical series of benzo [b] [1,4]oxazepin-4-one analogs [11] that proved to be effective anti-necroptosis agents.…”

Section: Introductionmentioning

confidence: 99%

Discovery of simplified benzazole fragments derived from the marine benzosceptrin B as necroptosis inhibitors involving the receptor interacting protein Kinase-1

Benchekroun

Ermolenko

Tran

et al. 2020

European Journal of Medicinal Chemistry

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Highlights ➢ Design, synthesis of Benzosceptrin C-derived compounds as new necroptosis inhibitors. ➢ SAR study on the 54 benzazoles on the TNF-α induced necroptosis in human Jurkat FADD-deficient cells. ➢ Compounds AV123 (12) and MBM105 (67) inhibited RIPK1 with IC50 values of 12.12 and 2.89 µM, respectively. ➢ Potent, non-toxic and selective MBM105 (67) blocked the necroptotic but not the apoptotic cell death.

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Small-Molecule Inhibitors of Necroptosis: Current Status and Perspectives

Cited by 64 publications

References 130 publications

Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis

Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis

The role of RIPK3‐regulated cell death pathways and necroptosis in the pathogenesis of cardiac ischaemia‐reperfusion injury

Discovery of simplified benzazole fragments derived from the marine benzosceptrin B as necroptosis inhibitors involving the receptor interacting protein Kinase-1

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