Identification of Novel Cyclobutane-Based Derivatives as Potent Acetyl-CoA Carboxylase Allosteric Inhibitors for Nonalcoholic Steatohepatitis Drug Discovery

作者：Yazhou Wang, Hai Wang, Qingqing Li, Ying Zhang, Rupeng Dai, Jun Wu, Yanan Zhang, Xiaomeng Zhang, Liwen Zhao, Jian Liu · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00259 · 被引用次数：3 · 研究领域：Liver Disease Diagnosis and Treatment、Diet, Metabolism, and Disease、Metabolomics and Mass Spectrometry Studies

Nonalcoholic steatohepatitis (NASH) has become a leading cause of liver fibrosis and hepatocellular carcinoma; however, there are no efficient drugs for NASH therapy. Acetyl-CoA carboxylase (ACC) is a crucial enzyme regulating lipid metabolism that is considered as a potential target for NASH treatment. Allosteric inhibitors target nonfunctional sites, which tend to be highly variable in protein families; thus, allosteric inhibitors are explored as an important source of drug candidates. Herein, several hotspot residues are initially identified by utilizing molecular dynamic simulation, MM-GBSA calculation, and alanine mutation. Then, focusing on the interaction with hotspot residues, several cyclobutane-based ACC allosteric inhibitors are designed, synthesized, and biologically evaluated. Among them, B1 demonstrates potent ACC inhibitory activity in vitro, a higher distribution in liver than in other tissues, and a potent therapeutic effect for NASH in vivo, making it a promising candidate for the treatment of NASH.