HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis

Park, Han-Hee; Park, Sung Yong; Mah, Shinmee; Park, Junghee; Hong, Soon‐Sun; Hong, Sungwoo; Kim, You‐Sun

doi:10.1038/s12276-018-0152-8

Cited by 39 publications

(32 citation statements)

References 41 publications

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“…59,60 Thus, it is possible that the increased protection by breast milk and 2'FL over Nec1s may be a result of inhibition of necroptosis downstream of RIPK1, or the result of inhibition of synergetic necroptosis-apoptosis cross-talk as discussed earlier. Future studies using specific RIPK3 inhibitors 60,61 or MLKL inhibitors with known activity in human tissue [62][63][64] may be useful in sorting out this potential branch point at RIPK3 and establishing if there is any communication between necroptosis and apoptosis in this disease.…”

Section: Discussionmentioning

confidence: 99%

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

Werts

Fulton

Ladd

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Necrotizing enterocolitis is a devastating disease of prematurity characterized by gram-negative bacteria colonization and enterocyte death. We identify a role of Toll-like receptor 4-mediated necroptosis of the intestinal epithelium as a precursor to necrotizing enterocolitis development. BACKGROUND & AIMS: Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by Toll-like receptor 4 (TLR4)-dependent intestinal inflammation and enterocyte death. Given that necroptosis is a proinflammatory cell death process that is linked to bacterial signaling, we investigated its potential role in NEC, and the mechanisms involved. METHODS: Human and mouse NEC intestine were analyzed for necroptosis gene expression (ie, RIPK1, RIPK3, and MLKL), and protein activation (phosphorylated RIPK3). To evaluate a potential role for necroptosis in NEC, the effects of genetic (ie, Ripk3 knockout or Mlkl knockout) or pharmacologic (ie, Nec1s) inhibition of intestinal inflammation were assessed in a mouse NEC model, and a possible upstream role of TLR4 was assessed in Tlr4-deficient mice. The NEC-protective effects of human breast milk and its constituent milk oligosaccharides on necroptosis were assessed in a NEC-in-a-dish model, in which mouse intestinal organoids were cultured as either undifferentiated or differentiated epithelium in the presence of NEC bacteria and hypoxia. RESULTS: Necroptosis was activated in the intestines of human and mouse NEC in a TLR4-dependent manner, and was upregulated specifically in differentiated epithelium of the immature ileum. Inhibition of necroptosis genetically and pharmacologically reduced intestinal-epithelial cell death and mucosal inflammation in experimental NEC, and ex vivo in the NEC-in-a-dish system. Strikingly, the addition of human breast milk, or the human milk oligosaccharide 2 fucosyllactose in the ex vivo system, reduced necroptosis and inflammation. CONCLUSIONS: Necroptosis is activated in the intestinal epithelium upon TLR4 signaling and is required for NEC development, and explains in part the protective effects of breast milk.

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Section: Discussionmentioning

confidence: 99%

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

Werts

Fulton

Ladd

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…Dabrafenib has been advanced into clinical trials for melanoma treatment (Table 3). Recently, HS-1371 was identified as a novel specific RIPK3 inhibitor which binds to the ATP-binding pocket of RIPK3 and inhibits kinase activity [47]. In addition, ponatinib and pazopanib have been found to specifically block necroptosis, but not apoptosis by targeting RIPK1/3 in human cells [43], and they were also recently proposed as possible candidates in clinical therapy of various cancer types as listed in Table 3.…”

Section: Ripk3 Plays a Key Role In Necroptosismentioning

confidence: 99%

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

Chen

Garssen

et al. 2019

Cells

129

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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“…Additionally, the ASC-NLRP3 inflammasome can also directly activate RIPK3 (independent of RIPK1) leading to MLKL activation and subsequent necroptosis [ 45 ]. Current in vivo therapy development efforts have revolved around inhibition of principally necroptosis and its key components RIPK3 and MLKL [ 64 , 65 , 66 , 67 ]. Early study highlighted the beneficial effects of RIPK3 and MLKL inhibitors on inflammation in animal models of disease ranging from ischemic injury to autoimmune disorders and neoplasia [ 68 , 69 ].…”

Section: Discussionmentioning

confidence: 99%

Lytic Cell Death Mechanisms in Human Respiratory Syncytial Virus-Infected Macrophages: Roles of Pyroptosis and Necroptosis

Bedient

Pokharel

Chiok

et al. 2020

Viruses

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Human respiratory syncytial virus (RSV) is the most common cause of viral bronchiolitis and pneumonia in infants and children worldwide. Inflammation induced by RSV infection is responsible for its hallmark manifestation of bronchiolitis and pneumonia. The cellular debris created through lytic cell death of infected cells is a potent initiator of this inflammation. Macrophages are known to play a pivotal role in the early innate immune and inflammatory response to viral pathogens. However, the lytic cell death mechanisms associated with RSV infection in macrophages remains unknown. Two distinct mechanisms involved in lytic cell death are pyroptosis and necroptosis. Our studies revealed that RSV induces lytic cell death in macrophages via both of these mechanisms, specifically through the ASC (Apoptosis-associated speck like protein containing a caspase recruitment domain)-NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome activation of both caspase-1 dependent pyroptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3), as well as a mixed lineage kinase domain like pseudokinase (MLKL)-dependent necroptosis. In addition, we demonstrated an important role of reactive oxygen species (ROS) during lytic cell death of RSV-infected macrophages.

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HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis

Cited by 39 publications

References 41 publications

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis

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

Lytic Cell Death Mechanisms in Human Respiratory Syncytial Virus-Infected Macrophages: Roles of Pyroptosis and Necroptosis

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