NASH Target Development Service for Acetyl-CoA Carboxylase (ACC) Inhibitors

Acetyl CoA carboxylase (ACC) inhibitors are important targets in non-alcoholic steatohepatitis (NASH) drug pipeline because of the essential role in regulating fatty acid metabolism. With years of exploration and development, Creative Biolabs has built a full range of small molecule drugs/antibody development platforms to discover new therapies for different diseases, including Drug discovery, Hit identification, Hit to Lead, Target Identification and Validation, Lead Optimization. Particularly, we are dedicated to developing and providing global customers with a diversiform portfolio of targets and therapeutic strategies for NASH.

Introduction of ACC Inhibitors

ACC is a complex multifunctional enzyme system that catalyzes the formation of malonyl-CoA by ATP-dependent carboxylation of acetyl-CoA. There are two isoforms of ACC, which show highly regulated tissue-specific expression patterns in humans. ACC1 is present in lipogenic tissues (liver and adipose), while ACC2 is expressed in oxidative tissues (liver, heart, and skeletal muscle). In our body, malonyl-CoA serves as a critical signal to regulate the synthesis and degradation of fatty acids - a shift that is sensitive to changes in diet and exercise and also controls the switch between carbohydrate and fatty acid utilization in the liver and skeletal muscle.

Fig.1 The reaction mechanism of acetyl CoA carboxylase.

Biochemicals that inhibit ACC have many applications in biochemical and physiological researches, which can result in inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. Therefore, inhibition of ACC has the potential to favorably affect a multitude of cardiovascular risk factors linked to obesity, diabetes, insulin resistance, and metabolic syndrome. Numerous studies have assessed the feasibility of ACC inhibitors for the prevention and/or treatment of various diseases and conditions.

ACC Inhibitors for the Treatment of NASH

NASH is a non-alcoholic fatty liver disease, which is characterized by the presence of hepatic steatosis, inflammation, hepatocyte ballooning, and variable degrees of fibrosis. Patients with advanced fibrosis from NASH are more likely to cause liver-related morbidity and mortality attributable to hepatic decompensation and hepatocellular carcinoma. Targeting different agents in fatty acids metabolism pathway and its downstream processes have become the effective treatment strategy for NASH.

Fig.2 NASH treatment market by geography.

The conversion of acetyl-CoA to malonyl-CoA by ACC is a rate-limiting step in de novo lipogenesis (DN L). Together with impaired fatty acid oxidation and generation of biologically active fatty acid signaling molecules, DN L has become an important factor in NASH pathogenesis. ACC inhibition may decrease hepatic steatosis, inflammation, and insulin resistance, supporting ACC inhibitors as potentially attractive therapeutic targets in NASH.

Several ACC inhibitors have been studied as attractive therapeutic strategies for NASH through simultaneous inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. NDI-010976 is an allosteric inhibitor of ACC1 and ACC2, which reduces hepatic DN L and favorably affects steatosis, inflammation, and fibrosis in animal models of fatty liver disease. GS-0976, a liver-targeted, small-molecule allosteric inhibitor of ACC1 and ACC2, inhibits hepatic DN L with a dose-dependent manner, indicating its potential in development for the treatment of NASH. ND-654, a liver-specific ACC inhibitor, reduces neutrophil recruitment and improves HCC survival. Therefore, ACC inhibitors could contribute considerable values to the treatment algorithm of NASH characterized by dysregulated fatty acid metabolism.

Fig.3 ND-654 reduces neutrophil recruitment and improves HCC survival. (Lally, 2019)

As a biological company dedicated to drug development and human health research, Creative Biolabs is devoted to finding more effective pharmaceutical candidates and therapies for NASH. At present, we can provide comprehensive ACC inhibitors and other useful target biomarkers for NASH treatment. In addition, we can offer customized design service to meet every specific demand. Our NASH services include but not limited to:

If you have any other requests for NASH services, please feel free to contact us or directly send us a quote.

Reference

Lally, J.S.V.; et al. Inhibition of Acetyl-CoA carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma. Cell metabolism. 2019, 29(1): 174-182.

For Research Use Only.