Lexicon Pharmaceuticals has announced the publication of preclinical data validating Acyl-CoA Synthetase 5 (ACSL5) as a target for obesity and chronic weight management.
The paper, titled ‘Acyl-CoA Synthetase 5 knockout and inhibitors protect against diet-induced obesity in mice by activating the ileal brake,’ was published online in the Journal of the Endocrine Society.
ACSL5 is an enzyme encoded by the Acsl5 gene that plays a vital role in lipid metabolism and is the target of LX9851, the Company’s investigational non-incretin, oral, small molecule ACSL5 inhibitor.
Animal model data showed that mice genetically modified to lack the ACSL5 gene exhibited favourable metabolic characteristics, including reduced body fat and conserved lean body mass.
In March 2025, Lexicon entered into an exclusive, worldwide licensing agreement for LX9851 with Novo Nordisk.
Preclinical research findings
Lexicon scientists generated mice with the ACSL5 gene deleted (knocked out) globally. These ACSL5 knockout mice had lower body fat, triglycerides, total cholesterol, and blood glucose as well as conserved lean body mass compared with mice carrying the ACSL5 gene.
Additionally, ACSL5 knockout mice had lower body weight and body fat while maintaining their lean body mass when fed a high-fat diet.
Similar effects were also observed when potent, small molecule inhibitors of ACSL5 were administered orally to mice with diet-induced obesity.
Mechanistic studies demonstrated that the favourable metabolic characteristics observed were by activating the ileal brake mechanism which delayed gastric emptying and decreased food consumption.
About LX9851
LX9851 is a first-in-class, non-incretin, oral, small molecule inhibitor of acyl-CoA synthetase 5 (ACSL5) for the treatment of obesity and associated cardiometabolic disorders.
Lexicon scientists identified the function of ACSL5, the target of LX9851, based on their discovery that knockout mice lacking the target enzyme exhibited favourable phenotypes across multiple measures of metabolic syndrome in preclinical models, including resistance to diet-induced obesity and improved body composition.
Lexicon has investigated the pharmacology of LX9851 as a stand-alone therapy and in combination with GLP-1 agonists such as semaglutide.
