Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein

Yan, Bo; Liu, Lei; Huang, Shiyao; Ren, Yan; Wang, Huayi; Yao, Ziheng; Lin, Li; Chen, She; Wang, Xiaodong; Zhang, Zhiyuan

doi:10.1039/c7cc00667e

Cited by 65 publications

(74 citation statements)

References 18 publications

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“…To this end, we examined the role of necroptosis in an A. fumigatus extract ( Asp . )‐induced allergic airway inflammation, using a recently discovered murine necroptosis inhibitor, GW80 . Treatment with GW80 resulted in delayed cell death kinetics for TSZ‐, but not TS‐, treated IL‐33‐GFP‐expressing L929 or HaCaT cells, thus confirming its ability to inhibit necroptotic cell death in vitro (Fig.…”

Section: Resultsmentioning

confidence: 62%

Necroptosis directly induces the release of full‐length biologically active IL‐33 in vitro and in an inflammatory disease model

et al. 2019

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Interleukin‐33 (IL‐33) is a pro‐inflammatory cytokine that plays a significant role in inflammatory diseases by activating immune cells to induce type 2 immune responses upon its release. Although IL‐33 is known to be released during tissue damage, its exact release mechanism is not yet fully understood. Previously, we have shown that cleaved IL‐33 can be detected in the plasma and epithelium of Ripk1−/− neonates, which succumb to systemic inflammation driven by spontaneous receptor‐interacting protein kinase‐3 (RIPK3)‐dependent necroptotic cell death, shortly after birth. Thus, we hypothesized that necroptosis, a RIPK3/mixed lineage kinase‐like protein (MLKL)‐dependent, caspase‐independent cell death pathway controls IL‐33 release. Here, we show that necroptosis directly induces the release of nuclear IL‐33 in its full‐length form. Unlike the necroptosis executioner protein, MLKL, which was released in its active phosphorylated form in extracellular vesicles, IL‐33 was released directly into the supernatant. Importantly, full‐length IL‐33 released in response to necroptosis was found to be bioactive, as it was able to activate basophils and eosinophils. Finally, the human and murine necroptosis inhibitor, GW806742X, blocked necroptosis and IL‐33 release in vitro and reduced eosinophilia in Aspergillus fumigatus extract‐induced asthma in vivo, an allergic inflammation model that is highly dependent on IL‐33. Collectively, these data establish for the first time, necroptosis as a direct mechanism for IL‐33 release, a finding that may have major implications in type 2 immune responses.

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Section: Resultsmentioning

confidence: 62%

Necroptosis directly induces the release of full‐length biologically active IL‐33 in vitro and in an inflammatory disease model

et al. 2019

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“…This report presented the first example of the use of LC‐MS/MS to identify an MLKL inhibitor. Compound 15 inhibits the oligomerization and translocation of MLKL to the cell membrane (Yan et al ., ). The discovery of the novel and potent MLKL inhibitor reported here will almost certainly be beneficial in exploring the biological function of MLKL, including its role in necroptosis‐related heart disease pathogenesis (Yan et al ., ).…”

Section: Therapeutic Opportunities Of Regulated Necrosis In Cardiac Dmentioning

confidence: 97%

“…Recently, Yan et al . () identified a novel MLKL inhibitor, compound 15 (TC13172), by phenotypic screening (Figure and Table ). This report presented the first example of the use of LC‐MS/MS to identify an MLKL inhibitor.…”

Section: Therapeutic Opportunities Of Regulated Necrosis In Cardiac Dmentioning

confidence: 99%

Programmed necrosis in cardiomyocytes: mitochondria, death receptors and beyond

Zhang

Liu

Zhang

et al. 2018

British J Pharmacology

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Excessive death of cardiac myocytes leads to many cardiac diseases, including myocardial infarction, arrhythmia, heart failure and sudden cardiac death. For the last several decades, most work on cell death has focused on apoptosis, which is generally considered as the only form of regulated cell death, whereas necrosis has been regarded to be an unregulated process. Recent findings reveal that necrosis also occurs in a regulated manner and that it is closely related to the physiology and pathophysiology of many organs, including the heart. The recognition of necrosis as a regulated process mandates a re‐examination of cell death in the heart together with the mechanisms and therapy of cardiac diseases. In this study, we summarize the regulatory mechanisms of the programmed necrosis of cardiomyocytes, that is, the intrinsic (mitochondrial) and extrinsic (death receptor) pathways. Furthermore, the role of this programmed necrosis in various heart diseases is also delineated. Finally, we describe the currently known pharmacological inhibitors of several of the key regulatory molecules of regulated cell necrosis and the opportunities for their therapeutic use in cardiac disease. We intend to systemically summarize the recent progresses in the regulation and pathological significance of programmed cardiomyocyte necrosis along with its potential therapeutic applications to cardiac diseases. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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“…These inhibitors abrogate the plasma membrane association, which is vital for MLKL functioning. GW806742X was found to be able to directly bind the KLD of MLKL and therefore block MLKL phosphorylation, oligomerization and plasma membrane translocation [48].…”

Section: Mlkl Is the Effector Protein In Necroptosismentioning

confidence: 99%

Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

Chen

Garssen

et al. 2019

Cells

122

115

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Necroptosis, or regulated necrosis, is an important type of programmed cell death in addition to apoptosis. Necroptosis induction leads to cell membrane disruption, inflammation and vascularization. It plays important roles in various pathological processes, including neurodegeneration, inflammatory diseases, multiple cancers, and kidney injury. The molecular regulation of necroptotic pathway has been intensively studied in recent years. Necroptosis can be triggered by multiple stimuli and this pathway is regulated through activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3 and pseudokinase mixed lineage kinase domain-like (MLKL). A better understanding of the mechanism of regulation of necroptosis will further aid to the development of novel drugs for necroptosis-associated human diseases. In this review, we focus on new insights in the regulatory machinery of necroptosis. We further discuss the role of necroptosis in different pathologies, its potential as a therapeutic target and the current status of clinical development of drugs interfering in the necroptotic pathway.

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Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein

Cited by 65 publications

References 18 publications

Necroptosis directly induces the release of full‐length biologically active IL‐33 in vitro and in an inflammatory disease model

Necroptosis directly induces the release of full‐length biologically active IL‐33 in vitro and in an inflammatory disease model

Programmed necrosis in cardiomyocytes: mitochondria, death receptors and beyond

Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

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