NASH Target Development Service for Stearoyl-CoA Desaturase (SCD) Inhibitors

Stearoyl-CoA desaturase (SCD) is a key enzyme that functions in the formation of monounsaturated fatty acids (MUFAs). It has been reported that SCD inhibitors are promising therapeutic agents for NASH. Creative Biolabs is an undisputed service provider in drug discovery. We are able to provide first-in-class target screening, structural characterization, and functional profiling services for identification of potential drug targets.

Role of SCD in NASH

SCD belongs to the fatty acid desaturase family and is an integral membrane protein located in the endoplasmic reticulum. There are four isoforms (SCD1-4) found in mouse. Only 2 SCD isoforms, SCD1 and SCD5, are found in human. These SCD isoforms are required for the biosynthesis of MUFAs. They catalyze the desaturation of saturated fatty acids which are either synthesized de novo or derived from the diet. MUFAs, the products of SCD, have been implicated to serve as the substrates for the synthesis of various kinds of lipids (such as phospholipids and triglycerides), and the regulators in signal transduction and differentiation. The abnormality of SCD may influence various physiological and pathological processes, including cellular differentiation, insulin sensitivity, metabolic syndrome, atherosclerosis, cancer, obesity, and nonalcoholic steatohepatitis (NASH). SCD-1 deficiency can lead to decreased body adiposity, increased insulin sensitivity, and resistance to diet-induced obesity. Moreover, the activity of hepatic SCD is increased in nonalcoholic fatty liver disease (NAFLD).

Fig.1 The pathway of electron transfer in the desaturation of saturated fatty acids by SCD. (Uto, 2016)

SCD Inhibitors in NASH Therapy

Because SCD exerts an essential role in the various pathological processes, SCD has been regarded as a potential therapeutic target. Especially, SCD-1 is the critical control point regulating de novo lipogenesis, triglyceride synthesis, and fatty acid oxidation through the generation of MUFAs. SCD-1 inhibitors are claimed to be new treatments for various diseases, such as skin disorders, NASH, hepatitis C virus (HCV), Alzheimer's disease, cancer, obesity, diabetes, and other metabolic diseases. In experimental NASH models, a SCD-1 inhibitor, N-(2-hydroxy-2-phenylethyl)-6-[4-(2-methylbenzoyl) piperidin-1-yl] pyridazine-3-carboxamide, has shown to ameliorate hepatic triglyceride accumulation, liver injury, hepatocellular degeneration, and inflammation. Besides, SCD-1 inhibitors also exert increased insulin sensitivity and resistance to diet-induced obesity. Hence, SCD inhibitors are expected to be promising drugs for the treatment of NASH.

Fig.2 SCD1 is believed to have a central role in directing the flow of lipid substrates between storage and utilization in energy metabolism. (Zhang, 2013)

With years of experience in drug discovery, Creative Biolabs has become an outstanding service provider for the development of drugs targeting various diseases. We can offer comprehensive services covering drug target screening, identification, and functional profiling services. We also provide antibody development services for biomarkers for NASH diagnosis or therapeutical molecules development (e.g. Phage Display & Antibody Library Services, Antibody Analysis Services, Antibody Engineering Services). If you are interested in our services, please don’t hesitate to contact us for more details.

References

1. Uto, Y. Recent progress in the discovery and development of stearoyl CoA desaturase inhibitors. Chemistry & Physics of Lipids. 2016, 197: 3-12.
2. Zhang, Z.; et al. Opportunities and challenges in developing stearoyl-coenzyme a Desaturase-1 inhibitors as novel therapeutics for human disease: miniperspective. Journal of medicinal chemistry. 2013, 57(12): 5039-5056.