NASH Target Development Service for Inflammasome Inhibitors

Fatty liver disease caused by overweight with diabetes and high risk of heart attack, termed non-alcoholic steatohepatitis (NASH), is the most common serious liver disease, but there is no efficient treatment. The activation of a protein scaffold within cells termed the inflammasome has been found to play a critical role in NASH and is showed as a potential target. As a leading service provider in target identification for drug discovery, Creative Biolabs has years of experience in the identification of potential drug targets. Now we can produce high-quality inflammasome inhibitors for the treatment of NASH, our scientific team can help you with every step of the development process, from design to validation.

Introduction of Inflammasome

Inflammasomes consist of an upstream sensor protein of the NOD-like receptor (NLR) family, the adaptor protein ASC (apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain), and the downstream effector caspase-1, which are a group of cytosolic multiprotein complexes. So far, the NLR proteins include NLRP1, NLRP2, NLRP3, NLRP6, NLRP7, NLRC4. The HIN-200 family member AIM2 been found to initiate the formation of an inflammasome. During the stimulation of microbial or damage-associated molecular patterns, inflammasome can be assembled and results in the autocatalytic cleavage of caspase-1 and processing of pro-IL-1β and pro-IL-18 into their mature and bioactive forms. Inflammasome activity requires two sequential stimuli, the transcription of the proforms of IL-1β/IL-18 and the formation of the inflammasome complex. Recently, a study showed that the NLRP3 inflammasome is involved in the development and progression of NASH. Upon production of a mouse model of NASH, expression of inflammasome components was upregulated in the liver and inflammasome activation occurred in isolated hepatocytes.

Fig.1 Mechanisms of NLRP3 inflammasome activation. (Guo, 2015)

Inflammasome Inhibitors

NASH therapeutic drug development is very active and advancing rapidly. New drugs are being designed to target various intrahepatic sites, such as inflammasome inhibitors. Currently, several inflammasome inhibitors including the apoptosis signal-regulating kinase-1 (ASK-1) inhibitors, NF-κB inhibitors, ERK inhibitors, NLRP3 inflammasome inhibitors, and the MAP kinases inhibitors are under actively assessed for the NASH therapy and showing promising therapeutic effect.

• Apoptosis Signal-Regulating Kinase-1 (ASK-1) Inhibitors
  Ballooned hepatocytes are associated with the activation of apoptosis-related pathways, representing a hallmark of NASH and fibrosis progression. Under the condition of oxidative stress, activation of apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine signaling kinase, can induce phosphorylation of p38 mitogen-activated kinase and c-Jun N-terminal kinase (JNK), resulting in the activation of stress response pathways that aggravated hepatic inflammation, apoptosis, and fibrosis. Therefore, inhibition of ASK1 has been proposed as a target for the treatment of NASH. For example, in a murine model of NASH, selective inhibition of ASK1 by selonsertib (formerly GS-4997) not only significantly improved metabolic parameters involved in NASH but also reduced hepatic steatosis, inflammation, and fibrosis.

Fig.2 Mechanism of ASK1 regulation in NASH. (Schuster, 2017)

• NF-кB Inhibitors
  Activation of the dimeric transcription factor nuclear factor (NF-кB) is essential for the development of inflammation in a variety of conditions. Many evidence suggested that NF-кB activation may be a crucial factor resulting in the development of NASH and its progression to fibrosis. The NF-кB pathway has been confirmed to be upregulated both in rodent models and in patients with NASH, and mechanistic evidence has been displayed by studies in transgenic mice. Conditional activation of NF-кB within hepatocytes is competent to trigger low-grade liver inflammation, steatosis, and insulin resistance, while deletion of IKK2 preserves the sensitivity to insulin. These data and the typical role of NF-кB in inflammation have indicated that NF-кB inhibition as a possible strategy for the treatment of NASH. A study reported that a novel pharmacological inhibitor of IKK2, AS602868, was tested in a mouse model of NASH, induced by administration of a high sucrose diet containing orotic acid, which impairs triglyceride secretion by hepatocytes. The daily administration of the IKK2 inhibitor can significantly ameliorate steatosis and the proinflammatory response.
• ERK Inhibitors
  Extracellular signal-regulated kinases (ERKs) are widely expressed protein kinase intracellular signaling molecules involved in functions including the regulation of meiosis, mitosis, and postmitotic in differentiated cells. The ERK pathway has been found associated with the process of NASH, which indicated that the ERK signal could be acted as a potential target to treat the disease. Studies have showed that the expression of extracellular signal-regulated kinase (ERK) and NF-B is significantly up-regulated during NASH. Therefore, targeting ERK pathways represent a novel treatment strategy for NASH treatment.
• NLRP3 Inflammasome Inhibitors
  Inflammasome NLRP3 has been suggested to play a critical role in NASH. To date, a drug called MCC-950 which has already been shown to block NLRP3 activation in an attempt to reduce liver injury in NASH. Results showed that this drug partly reversed liver inflammation, particularly in obese diabetic mice that most closely resemble the human context of NASH. In addition, such inhibition of liver inflammation in NASH achieved with MCC950 partly reversed liver scarring, the process that links NASH to development of cirrhosis.
• MAP Kinases Inhibitors
  A MAP kinase (mitogen-activated protein kinase) is a type of protein kinase involved in directing cellular responses to a diverse array of stimuli. They play roles in proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis. Indeed, the MAP kinase actively participates in the NASH, which has been regarded as a target for NASH therapeutic.

Features

• Advanced technology
• Rational design and strategy
• Fast target identification and validation service
• Pre-made library screening
• High-quality and cost-effective

As the undisrupted global leader in the disease target development, Creative Biolabs has successfully finished lots of target construction and custom target screening services against various biomarkers for our clients all over the world. We are therefore confident in offering the best service and high-efficient products such as inflammasome inhibitors. If you are interested in our NASH-associated service, please do not hesitate to contact us for more details.

References

1. Guo, H.; et al. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nature Medicine. 2015, 21(7): 677-687.
2. Schuster, S.; Feldstein, A.E. Nash: novel therapeutic strategies targeting ask1 in nash. Nature Reviews Gastroenterology & Hepatology. 2017.

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