SREBP inhibitors: an updated patent review for 2008-present

ABSTRACT

Introduction

Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-binding transcription factors that activate genes encoding enzymes required for cholesterol and unsaturated fatty acid synthesis. Overactivation of SREBP is related to the occurrence and development of diabetes, nonalcoholic fatty liver, tumor, and other diseases. In the past period, many SREBP inhibitors have been found.

Areas covered

This manuscript is a patent review of SREBP inhibitors. We searched 2008 to date for all data from the US patent database (https://www.uspto.gov/) and the European patent database (https://www.epo.org/) with ‘SREBP’ and ‘inhibitor’ as keywords and analyzed the search results.

Expert opinion

Both synthetic and natural SREBP inhibitors have been reported. Despite the lack of cocrystal structure of SREBP inhibitor, the mechanisms of several compounds have been clarified. Importantly, some SREBP inhibitors have been proved to have good activity in preclinical studies. As the characteristics of lipid metabolism reprogramming in cardio-cerebrovascular diseases and tumors are gradually revealed, more and more attention will be focused on SREBP.

KEYWORDS:

• SREBP
• inhibitors
• lipid
• metabolism
• transcription factor

Article highlights

• SREBP is the core transcription factor of lipid metabolism regulation. SREBP inhibitors are potential therapeutic drugs for nonalcoholic fatty liver, tumor, and other diseases.

• Fatostatin has shown high activity in preclinical studies, but its low solubility limits its use.

• A series of studies were carried out to reconstruct the structure of Fatostatin, and some of them had better activity and pharmacokinetic properties.

• Steroid derivatives including vitamin D are important lead compounds of SREBP inhibitors.

• The lack of crystal structure and clinical data are the main bottlenecks limiting the development of SREBP inhibitors.

Declaration of interests

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.

Author contribution statement

Yiliang Li and Wenbin Hou visualized the current idea and gathered patent-related information. Zhenyu Peng, Leyuan Chen, Huiqiang Wei, and Feifei Xu contributed toward the drafting and finalization of the manuscript. Manjiang Wang and Xufan Yue contributed toward the literature survey. All authors approved the final version of the manuscript.

Additional information

Funding

The work was supported in part by the National Natural Science Foundation of China (Grant No. 82104012 & 82202950), the Fundamental Research Funds for the Central Universities (3332022063), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-042), and the Chinese Academy of Medical Sciences Innovation Fund for National Medical Health Science and Technology Platform (2022-I2M-2-003).