SIMM discovered novel AMPK allosteric activators with beneficial effects on diabetic mice----Shanghai Institute of Materia Medica, Chinese Academy of Sciences

AMP-activated protein kinase (AMPK) is an energy sensor of metabolism that is an attractive therapeutic target for type 2 diabetes mellitus and metabolic syndrome. Many drugs that show beneficial effects on metabolic syndrome exert their effects partly through the indirect activation of AMPK. However, there are not many AMPK small-molecule direct activators discovered so far.

Using a novel homogeneous scintillation proximity assay (SPA), and through structure optimization and random screening, researchers at SIMM have discovered two novel AMPK allosteric activators. These findings provide new tools for understanding the allosteric activation of AMPK and suggest that the direct activation of AMPK is a promising approach for discovering novel therapies for the treatment of type 2 diabetes mellitus and metabolic diseases.

Using a SPA assay, researchers identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. C24 allosterically stimulated inactive AMPK α subunit truncations and activated AMPK heterotrimers in molecular level. In hepatocytes, C24 increased the phosphorylation of AMPK without changing intracellular AMP/ATP ratio, it decreased glucose output and triglyceride content. Chronic oral treatment with C24 significantly reduced blood glucose, lipid levels, and also shows other beneficial effects on db/db and diet induced obesity (DIO) mice.

This research work was performed by Dr. LI Yuanyuan, Dr. YU Lifang and colleagues, and supervised by Professor NAN Fajun, Professor LI Jia and Professor LI Jingya. The chemistry part has been published in the journal ACS Medicinal Chemistry Letters (ACS Med Chem Lett, 2013, 4:475-480) and biology part in the journal of Toxicology and Applied Pharmacology.

Besides, through random screening, researchers also discovered another small-molecule AMPK allosteric activator, ZLN024, which activated 4 combinations of AMPK heterotrimers and inhibited AMPK dephosphorylation in molecular level. ZLN024 activated AMPK in myotubes and hepatocytes without increasing the ADP/ATP ratio. It stimulated glucose uptake and fatty acid oxidation, decreased fatty acid synthesis and glucose output. Chronic oral treatment with C24 improved glucose tolerance and reduced fatty liver.
This research work was performed by Dr. ZHANG Lina and colleagues, and supervised by Professors SHEN Jingkang, LI Jia and LI Jingya. It has been published in the journal of PLOS ONE.

Full text

Image by SIMM