1145-P: Development of MLX-0871, a Potent, Isoform-Selective, Orally Available AMPK Activator, Displays Efficacy in Obese and Type 2 Diabetes Models

Introduction & Objective: AMPK is a αβγ heterotrimeric Ser/Thr kinase that acts as a cellular energy sensor and is activated by upstream enzymes when the cellular ratio of AMP to ATP is elevated due to nutrient deprivation. AMPK activity can be altered due to many physiological factors, such as hormones, cytokines, dietary nutrients, and pathological conditions, such as obesity, chronic inflammation, and type 2 diabetes. AMPK activation can lead to lower hepatic glucose and plasma glucose levels. Thus, AMPK is an attractive target for treating various metabolic diseases.

Methods: 12 isoforms of AMPK in activation mode using radiometric HotSpot^TM assay. Glucose Uptake and Western Blot cell-based assays were conducted in human skeletal muscle, upper arm, white preadipocyte, abdomen, and hepatocyte cells. Male C57BL/6 DIO mice aged 20 weeks were fed with a high-fat diet (60 kcal%) for 14 weeks before initiating the experiment. A vehicle group was compared to two dose levels of 10 and 30 mg/kg, dosed orally for the 30-day treatment, with weight loss and serum glucose regulation measured at regular intervals.

Results: MLX-0871, MLX-0867, and analogs are orally available small molecule AMPK activators that have been shown to stimulate AMPK activity and enhance glucose uptake in human tissues dose-dependently. MLX-0871 and MLX-0867 do not cause any AMPK activation in healthy, obese, and diabetic patient cardiac muscle tissue samples and suggest selectivity to skeletal muscle. MLX compounds demonstrated safety and tissue specificity. Preclinical studies suggest that MLX-0871 may have therapeutic potential in the treatment of metabolic disorders such as obesity and type 2 diabetes.

Conclusion: These results suggest that AMPK activators induce insulin modulation and improve oxidative muscle function in obese and type 2 diabetes patient samples. In vitro data supporting studies will be presented, including DIO and db/db efficacy results.