Discovery and development of ASK1 inhibitors

Brys, Reginald; Gibson, Karl R.; Poljak, Tanja; Plas, Steven Van der; Amantini, David

doi:10.1016/bs.pmch.2020.02.001

Cited by 22 publications

(9 citation statements)

References 225 publications

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“…Studies have found that the binding of Nacetylgalactosaminyltransferase-4 to ASK1 inhibits its N-terminal dimerization and subsequent phosphorylation, thus leading to strong inactivation of downstream JNK/p38 signaling [47] . Moreover, the therapeutic use of ASK1 inhibitors has been extensively described in several reviews [13,[48][49][50] . Selonsertib (gs-4997) is a selective ASK1 inhibitor that reduces metabolic parameters, inflammation and fibrosis in multidrug resistance and non-alcoholic hepatitis [51,52] .…”

Section: Discussionmentioning

confidence: 99%

Thioredoxin-interacting protein deficiency protects against severe acute pancreatitis by suppressing apoptosis signal-regulating kinase 1

Zhu

Liu

et al. 2022

Preprint

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Acute pancreatitis is a common acute inflammatory abdominal disease. When acute pancreatitis progresses to severe acute pancreatitis (SAP), it can lead to systemic inflammation and even multiple organ failure. Thioredoxin-interacting protein (TXNIP) is an important protein involved in redox reactions of the inflammatory response. However, the specific role of TXNIP in SAP remains unclear. In this study, we investigated the role of thioredoxin interacting protein (TXNIP) in acute pancreatitis when induced by high doses of arginine. We found that pancreatic damage and the inflammatory response associated with acute pancreatitis were largely restrained in TXNIP knock-out mice but were enhanced in mice overexpressing TXNIP. Interestingly, the phosphorylation of p38, JNK, and ASK1 diminished in TXNIP-KO mice with pancreatitis in comparison with wild-type mice. The role of oxidative stress in SAP was explored in two models: TXNIP and AVV-TXNIP. TXNIP knockdown or the inhibition of ASK1 by gs-4997 abrogated the increase in p-p38, p-JNK, and p-ASK1 in AR42J cells incubated with L-Arg. The administration of gs-4997 to mice with pancreatitis largely reduced the upregulation of IL-6, IL-1β, TNF-α and MCP-1. Systemic inflammatory reactions and injury in the lungs and kidneys were assessed in TXNIP-KO and AVV-TXNIP mice with expected outcomes. In conclusion, TXNIP is a novel mediator of SAP and exerts action by regulating inflammatory responses and oxidative stress via the ASK1-dependent activation of the JNK/p38 pathways. Thus, targeting TXNIP may represent a promising approach to protect against SAP.

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Section: Discussionmentioning

confidence: 99%

Thioredoxin-interacting protein deficiency protects against severe acute pancreatitis by suppressing apoptosis signal-regulating kinase 1

Zhu

Liu

et al. 2022

Preprint

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“…Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) and, therefore, an upstream member of the MAPK signaling pathway that regulates p38 and JNK. As a converging point of cell stress signaling, inhibition of ASK1 is of interest for many human diseases, including chronic pain management [ 60 , 61 ]. In recent examples, ASK1 inhibitors GS-4997 (selonsertib) [ 62 ] and NQDI1 [ 63 ] attenuated mechanical allodynia and thermal hyperalgesia induced by CCI of the sciatic nerve in rats [ 64 , 65 ] ( Figure 15 ).…”

Section: Cmgc Groupmentioning

confidence: 99%

Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

et al. 2021

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The purpose of this review is to underline the protein kinases that have been established, either in fundamental approach or clinical trials, as potential biological targets in pain management. Protein kinases are presented according to their group in the human kinome: TK (Trk, RET, EGFR, JAK, VEGFR, SFK, BCR–Abl), CMGC (p38 MAPK, MEK, ERK, JNK, ASK1, CDK, CLK2, DYRK1A, GSK3, CK2), AGC (PKA, PKB, PKC, PKMζ, PKG, ROCK), CAMK, CK1 and atypical/other protein kinases (IKK, mTOR). Examples of small molecule inhibitors of these biological targets, demonstrating an analgesic effect, are described. Altogether, this review demonstrates the fundamental role that protein kinase inhibitors could play in the development of new pain treatments.

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“…Apoptotic signal-regulated kinase 1 (ASK1) is one of the mediators of cell death induced by stimuli including reactive oxygen species, excessive calcium influx, and ischemia [ 98 ]. Phosphorylation of ASK1 at Thr845 is associated with ASK1 activation and consequent ASK1-dependent apoptosis [ 28 ].…”

Section: Ischemia Reperfusion Injury and Protein S-nitrosylationmentioning

confidence: 99%

Role of Nitric Oxide and Protein S-Nitrosylation in Ischemia-Reperfusion Injury

Lee

Choi

2021

Antioxidants

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Ischemia-reperfusion injury (IRI) is a process in which damage is induced in hypoxic tissue when oxygen supply is resumed after ischemia. During IRI, restoration of reduced nitric oxide (NO) levels may alleviate reperfusion injury in ischemic organs. The protective mechanism of NO is due to anti-inflammatory effects, antioxidant effects, and the regulation of cell signaling pathways. On the other hand, it is generally known that S-nitrosylation (SNO) mediates the detrimental or protective effect of NO depending on the action of the nitrosylated target protein, and this is also applied in the IRI process. In this review, the effect of each change of NO and SNO during the IRI process was investigated.

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Discovery and development of ASK1 inhibitors

Cited by 22 publications

References 225 publications

Thioredoxin-interacting protein deficiency protects against severe acute pancreatitis by suppressing apoptosis signal-regulating kinase 1

Thioredoxin-interacting protein deficiency protects against severe acute pancreatitis by suppressing apoptosis signal-regulating kinase 1

Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

Role of Nitric Oxide and Protein S-Nitrosylation in Ischemia-Reperfusion Injury

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