Necroptosis inhibitors as therapeutic targets in inflammation mediated disorders - a review of the current literature and patents

Kopalli, Spandana Rajendra; Kang, Tae-Bong; Koppula, Sushruta

doi:10.1080/13543776.2016.1230201

Cited by 24 publications

(23 citation statements)

References 124 publications

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“…Activated MLKL oligomers eventually cause membrane rupture and release of DAMPs, which trigger inflammatory reactions and accelerate cell death [25, 26]. Thus, necroptosis is recognized as a cause of inflammation and is linked to pathological conditions with an overt inflammatory signature [25]. Necroptosis execution depends on RIPK1, RIPK3, and MLKL activation, and can be blocked by these inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…When caspases are inhibited under certain physiological conditions, RIPK1 via the RIP-homotypic interaction motif (RHIM) interacts with downstream RIPK3 to form the necrosome to then recruit MLKL [24]. Activated MLKL oligomers eventually cause membrane rupture and release of DAMPs, which trigger inflammatory reactions and accelerate cell death [25, 26]. Thus, necroptosis is recognized as a cause of inflammation and is linked to pathological conditions with an overt inflammatory signature [25].…”

Section: Discussionmentioning

confidence: 99%

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Necroptosis Contributes to Urban Particulate Matter-Induced Airway Epithelial Injury

Luo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Necroptosis, a form of programmed necrosis, is involved in the pathologic process of several kinds of pulmonary diseases. However, the role of necroptosis in particulate matter (PM)–induced pulmonary injury remains unclear. The objective of this study is to investigate the involvement of necroptosis in the pathogenesis of PM-induced toxic effects in pulmonary inflammation and mucus hyperproduction, both in vitro and in vivo. Methods: PM was administered into human bronchial epithelial (HBE) cells or mouse airways, and the inflammatory response and mucus production were assessed. The mRNA expressions of IL6, IL8 and MUC5AC in HBE cells and Cxcl1, Cxcl2, and Gm-csf in the lung tissues were detected by quantitative real-time RT-PCR. The secreted protein levels of IL6 and IL8 in culture supernatants and Cxcl1, Cxcl2, and Gm-csf in bronchoalveolar lavage fluid (BALF) were detected by enzyme-linked immunosorbent assay (ELISA). We used Western blot to measure the protein expressions of necroptosis-related proteins (RIPK1, RIPK3, and Phospho-MLKL), NF-κB (P65 and PP65), AP-1 (P-c-Jun and P-c-Fos) and MUC5AC. Cell necrosis and mitochondrial ROS were detected using flow cytometry. In addition, pathological changes and scoring of lung tissue samples were monitored using hemoxylin and eosin (H&E), periodic acid-schiff (PAS) and immunohistochemistry staining. Results: Our study showed that PM exposure induced RIP and MLKL-dependent necroptosis in HBE cells and in mouse lungs. Managing the necroptosis inhibitor Necrostatin-1 (Nec-1) and GSK’872, specific molecule inhibitors of necroptosis, markedly reduced PM-induced inflammatory cytokines, e.g., IL6 and IL8, and MUC5AC in HBE cells. Similarly, administering Nec-1 significantly reduced airway inflammation and mucus hyperproduction in PM-exposed mice. Mechanistically, we found PM–induced necroptosis was mediated by mitochondrial reactive oxygen species-dependent early growth response gene 1, which ultimately promoted inflammation and mucin expression through nuclear factor κB and activator protein-1 pathways, respectively. Conclusions: Our results demonstrate that necroptosis is involved in the pathogenesis of PM–induced pulmonary inflammation and mucus hyperproduction, and suggests that it may be a novel target for treatment of airway disorders or disease exacerbations with airborne particulate pollution.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Necroptosis Contributes to Urban Particulate Matter-Induced Airway Epithelial Injury

Luo

et al. 2018

Cell Physiol Biochem

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“…Necroptosis, or programmed necrosis, is a form of cell death that causes inflammation by damaging cell function and/or releasing damage‐associated molecular patterns . Emerging evidence indicates that necroptosis may play a critical role in mediating a variety of human disease pathologies, including ischemia‐reperfusion injury, pancreatitis, myocardial infarction, atherosclerosis, liver disease, neurodegenerative disorders, and immune‐mediated inflammatory diseases such as inflammatory bowel diseases, rheumatoid arthritis, and psoriasis . Small‐molecule inhibitors of necroptosis are currently being developed as a new class of anti‐inflammatory agents with broad therapeutic potential …”

Section: Introductionmentioning

confidence: 99%

“…1 Emerging evidence indicates that necroptosis may play a critical role in mediating a variety of human disease pathologies, including ischemia-reperfusion injury, pancreatitis, myocardial infarction, atherosclerosis, liver disease, neurodegenerative disorders, and immune-mediated inflammatory diseases such as inflammatory bowel diseases, rheumatoid arthritis, and psoriasis. 2,3 Small-molecule inhibitors of necroptosis are currently being developed as a new class of anti-inflammatory agents with broad therapeutic potential. 3 Receptor-interacting protein kinase 1 (RIPK1) has emerged as an important therapeutic target for small-molecule kinase inhibitors because of its central role in mediating necroptosis in response to a variety of upstream activators, including the signaling that follows engagement of the tumor necrosis factor (TNF) receptor 1.…”

Section: Introductionmentioning

confidence: 99%

Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers

Weisel

Scott

Tompson

et al. 2017

Pharmacology Res & Perspec

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GSK2982772 is a highly selective inhibitor of receptor‐interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first‐in‐human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo‐controlled, double‐blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1‐120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open‐label relative bioavailability study comparing 20‐mg tablets vs capsules. Safety, tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were contact dermatitis and headache. Most AEs were mild in intensity, and there were no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the dose range studied (up to 120 mg BID). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24‐hour period for the 60‐mg and 120‐mg BID dosing regimens. Single and repeat doses of GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK1 TE support progression into Phase II clinical trials for further clinical development.

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“…Our present data enlarge the number of small chemical compounds having a potent necroptosis inhibitory activity [44]. Sib was also able to inhibit TRAIL-or FasL-induced necroptosis but not apoptosis regardless of the human or murine cell line origin.…”

Section: Discussionmentioning

confidence: 52%

Sibiriline, a new small chemical inhibitor of receptor‐interacting protein kinase 1, prevents immune‐dependent hepatitis

et al. 2017

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Necroptosis is a regulated form of cell death involved in several disease models including in particular liver diseases. Receptor-interacting protein kinases, RIPK1 and RIPK3, are the main serine/threonine kinases driving this cell death pathway. We screened a noncommercial, kinase-focused chemical library which allowed us to identify Sibiriline as a new inhibitor of necroptosis induced by tumor necrosis factor (TNF) in Fas-associated protein with death domain (FADD)-deficient Jurkat cells. Moreover, Sib inhibits necroptotic cell death induced by various death ligands in human or mouse cells while not protecting from caspase-dependent apoptosis. By using competition binding assay and recombinant kinase assays, we demonstrated that Sib is a rather specific competitive RIPK1 inhibitor. Molecular docking analysis shows that Sib is trapped closed to human RIPK1 adenosine triphosphate-binding site in a relatively hydrophobic pocket locking RIPK1 in an inactive conformation. In agreement with its RIPK1 inhibitory property, Sib inhibits both TNF-induced RIPK1-dependent necroptosis and RIPK1-dependent apoptosis. Finally, Sib protects mice from concanavalin A-induced hepatitis. These results reveal the small-molecule Sib as a new RIPK1 inhibitor potentially of interest for the treatment of immune-dependent hepatitis.

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Necroptosis inhibitors as therapeutic targets in inflammation mediated disorders - a review of the current literature and patents

Cited by 24 publications

References 124 publications

Necroptosis Contributes to Urban Particulate Matter-Induced Airway Epithelial Injury

Necroptosis Contributes to Urban Particulate Matter-Induced Airway Epithelial Injury

Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers

Sibiriline, a new small chemical inhibitor of receptor‐interacting protein kinase 1, prevents immune‐dependent hepatitis

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