Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors

ABSTRACT

Introduction: Acetyl-CoA Carboxylase (ACC) is an essential rate-limiting enzyme in fatty acid metabolism. For many years, ACC inhibitors have gained great attention for developing therapeutics for various human diseases including microbial infections, metabolic syndrome, obesity, diabetes, and cancer.

Areas covered: We present a comprehensive review and update of ACC inhibitors. We look at the current advance of ACC inhibitors in clinical studies and the implications in drug discovery. We searched ScienceDirect (https://www.sciencedirect.com/), ACS (https://pubs.acs.org/), Wiley (https://onlinelibrary.wiley.com/), NCBI (https://www.ncbi.nlm.nih.gov/) and World Health Organization (https://www.who.int/). The keywords used were Acetyl-CoA Carboxylase, lipid, inhibitors and metabolic syndrome. All documents were published before June 2019.

Expert opinion: The key regulatory role of ACC in fatty acid synthesis and oxidation pathways makes it an attractive target for various metabolic diseases. In particular, the combination of ACC inhibitors with other drugs is a new strategy for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Expanding the clinical indications for ACC inhibitors will be one of the hot directions in the future. It is also worth looking forward to exploring safe and efficient inhibitors that act on the BC domain of ACC.

KEYWORDS:

• Acetyl-CoA carboxylase
• lipid
• inhibitors
• metabolic syndrome

Article highlights

• ACC is a key regulator in the synthesis and oxidation of fatty acids, making it an attractive target for various metabolic diseases.

• There are few compounds that act directly on the BC domain of ACC, and it is worthwhile to develop compounds that interact with the BC domain.

• This review presents the studies by major pharmaceutical companies on the deployment of ACC inhibitors, including the discovery of different types of compounds, design considerations, and activity evaluations.

• Several ACC inhibitors have entered clinical studies, and this review provides a detailed discussion of the clinical findings of these drugs.

• Excessive inhibition of liver DNL by ACC inhibitors may cause elevation of plasma TGs. While PF-05221304 and GS-0976 do not excessively increase plasma TGs by moderately inhibiting liver DNL, their phase III clinical results will be instructive for the design of novel ACC inhibitors.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

Authors contributed equally to this paper.

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This article is supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS 2016-I2M-3-022 and 2017-I2M-3-019), Fundamental Research Funds for the Central Universities (No. 3332018117), the Science and Technology Project of Tianjin, China (No. 18ZXXYSY00110), and the Natural Science Foundation of Tianjin, China (No. 18JCQNJC09500).