NASH Target Development Service for mTOR Inhibitors

Non-alcoholic steatohepatitis (NASH) can cause liver fibrosis and cirrhosis, with final progression to hepatocellular carcinoma (HCC) in some cases. mTOR is the hub of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway, which is one of the most commonly mutated pathways in cancer. At present, it also has promising potential in the treatment of NASH. Creative Biolabs is a service provider with extensive experience and the high-end platform and state-of-the-art technology in NASH drug discovery (such as Target Identification and Validation, Hit identification, Hit to Lead, Lead Optimization, IND-Enabling and so on). We provide our clients with strategies targeting mTOR to help you find the novel treatment for NASH.

Introduction of mTOR Inhibitors

Mammalian/mechanistic target of rapamycin (mTOR) is an evolutionarily conserved intracellular serine-threonine kinase that regulates a wide range of functions, including cell growth, proliferation, survival, autophagy, lipid, and glucose metabolism. It belongs to the phosphoinositide 3-kinase-related kinase family and contains two functionally and structurally multiprotein distinct complexes: mTOR complex 1 (mTORC1) and mTORC2. mTORC1 is involved in protein synthesis and autophagy, as well as lipid synthesis, energy metabolism, and tumorigenesis. Compared with mTORC1, little is known about mTORC2, which may be related to cell survival/metabolism and cytoskeletal organization. The mTOR pathway has been identified as a key cellular signaling pathway and has become an exciting treatment target for various diseases. mTOR inhibitors, such as rapamycin, are being studied as potential treatments for various disorders. Currently, mTOR inhibitors are used as anticancer drugs against several solid tumors and immunosuppressive agents for transplantation of various organs. The most commonly used mTOR inhibitors are sirolimus (rapamycin) and everolimus. They act primarily on mTORC1 and exert their effects by inhibiting mTORC1 and downstream phosphorylation of its substrate, whereas their inhibitory effect on mTORC2 is mild.

mTOR Inhibitors for NASH

The mTOR pathway plays a key role in cellular metabolism, growth, and proliferation and has been evaluated as a target for the treatment of various malignancies as well as the NASH. Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that generates the second messenger phosphatidylinositol-3, 4, 5 trisphosphate (PIP3), which recruits protein kinase B (Akt) to the cell membrane. After Akt is activated, it regulates many downstream effectors, such as mTOR, which forms a stoichiometric complex with the raptor. Activation of the PI3K-Akt-mTOR pathway is associated with aberrant lipid metabolism. Therefore, the PI3K-Akt-mTOR pathway is currently inhibited by the use of inhibitors including LY294002 (PI3K inhibitor), rapamycin (mTOR inhibitor) and NVP-BEZ235 (the dual inhibitor of PI3K and mTOR). These inhibitors inhibit the PI3K-Akt-mTOR pathway, significantly inhibiting PI3K-Akt-mTOR downstream signaling while inducing the reduction of lipids accumulation, the decrease of lipogenesis, and the increase of fatty acids oxidation. Thus, the PI3K-Akt-mTOR inhibitors may provide additional therapeutic benefit to patients with NASH.

Fig.1 Overview of the PI3K-Akt-mTOR pathway and drug targets. (Dienstmann, 2014)

Creative Biolabs is a company focused on the development and commercialization of novel therapeutics for the treatment of NASH. Besides the service of target discovery and therapeutic strategies, we also provide biomarkers for NASH diagnosis and preclinical models of NASH, in order to better understand NASH and find a better treatment for NASH. Our service platform is a cost-effective and effective option for you to accelerate the development of drug targets. If you need any services about NASH, please feel free to contact us.

Reference

1. Dienstmann, R.; et al. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther. 2014, 13(5): 1021-31.