NASH Target Development Service for Hedgehog (Hh) Pathway Inhibitors

Nonalcoholic steatohepatitis (NASH), the most severe form of non-alcoholic fatty liver disease (NAFLD), is characterized by the presence of an abnormal accumulation of fat in the liver which in some individuals can progress to liver cell injury (hepatocellular ballooning) and inflammation. The hedgehog (Hh) pathway plays a role in the NASH process that can be a promising target for this disease treatment. Creative Biolabs is one of the best partners for scientists in the field of target-based drug discovery. As an experienced NASH drug discovery company, our scientists utilize a large variety of strategies that are designed to provide you Hh pathway inhibitors for NASH therapeutic. The goal of our services is to effectively save the time and cost of your drug discovery and production programs by taking advantage of our expertise and innovative technology platforms.

Introduction of Hedgehog (Hh) Pathway

The Hedgehog (Hh) pathway can transmit information to embryonic cells for proper cell differentiation. In mammals, there are three Hh homologs possessing different spatial and temporal distribution patterns: Desert hedgehog, Indian hedgehog (Ihh), and Sonic hedgehog (Shh). These proteins are modified by palmitoyl- and cholesterol and expressed by a number of different types of cells. They have functional specificity partly controlled by their regulatory mechanisms and the expression patterns in a given cell type. The Hh signaling pathway mainly consists of two transmembrane proteins: a signal receptor Patched (Ptch) and an essential signal activator Smoothened (Smo). An enduring mystery in Hh signaling in all animals revolves around the mechanism by which Ptch1 regulates Smo. In mammals, two isoforms of Ptch are encoded by Ptch1 and Ptch2. Only Ptch1 involves the activation of Hh signaling. In vivo, the Smo protein has either an inactive or active state, by its location within the cells, either inside or outside the primary cilium. The pathway also plays a role in the development of some cancers. To date, drugs specifically targeting Hedgehog signaling pathway to fight some diseases are being actively developed.

Fig.1 Model of the canonical Hedgehog signaling pathway in mammals. (Hui, 2013)

The Role of Hedgehog (Hh) Pathway Inhibitors in NASH

The Hh signaling pathway plays a critical role in the regulation of hepatic progenitor cell fate and liver development. In adults, the Hh pathway also regulates the regeneration and repair responses to liver injury. Hh signaling is repressed in normal healthy liver generally but is activated in liver diseases including liver fibrosis, NASH, hepatocellular carcinoma, and cholangiocarcinoma. Studies have found that the production of Shh ligand is increased significantly in the livers of patients with NAFLD. The Shh ligand produced by ballooned hepatocytes is known to stimulate hepatic stellate cells and fibroblasts through a paracrine mechanism, thereby enhancing a profibrogenic response in a mouse model of NASH. Recent studies have reported increased expression of Smo and Gli1 in primary hepatocytes from damaged livers, which suggested that Hh signaling in hepatocytes could be activated during liver injury and that this mechanism may contribute to hepatocyte regeneration and repair from liver injury. Therefore, the Hh pathway is a potential target for the treatment of the NASH disease.

Hedgehog (Hh) Pathway Inhibitors for NASH Treatment

Currently, several pharmacological Smo inhibitors (GDC-0449 and LED225) have been developed and assessed actively for targeting NASH therapy. After administration of Smo inhibitors to high-fat diet-fed wild-type mice, the number of activated macrophages expressed by pro-inflammatory cytokines (such as TNF-A, IL-1beta, monocyte chemoattractant protein 1 and IL-6) was significantly reduced. The Smo inhibitors were found to have variable effects on hepatic fat accumulation. In contrast, liver-specific deletion of Smo also inhibited macrophage activation and the expression of proinflammatory cytokine, while it did not significantly alter fat accumulation in the liver. Hence, the hedgehog (Hh) pathway inhibitors represent a type of promising strategy for NASH treatment.

Fig.2 Hedgehog signaling pathway demonstrating pharmacologic inhibitors of the signaling cascade and its molecular targets. (Tran, 2016)

Features

• Screening and profiling of a broad range of Hh pathway proteins
• Information on an essential family of signal proteins responsible for a wide range of on- and off-targeted biological processes
• Our unparalleled expertise and cutting-edge technologies have created an unprecedented and extremely competitive integrated NASH drug discovery platform

With years of expertise in this field, Creative Biolabs is dedicated to ensuring all services and results of Hh pathway inhibitors screening and profiling are at the highest level of quality. For the last 10 years, Creative Biolabs has delivered a plenty of services and products that meet the requirements of disease target screening and disease treatment. We are confident in accelerating your experimental progress and achieving ideal research goals with the most competitive price. If you are interested in our services, please do not hesitate to contact us for more details.

References

1. Hui, M.; et al. The hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy. Breast Cancer Research. 2013, 15(2).
2. Tran, B.A.P.; et al. Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review. Journal of Surgical Dermatology. 2016, 2(1): 23-34.