zln024 and Diabetes-Mellitus--Type-2

Type 2 diabetes mellitus is a complex metabolic disorder requiring polypharmacology approaches for effective treatment. Combinatorial library of fifteen new tricyclic benzimidazole derivatives have been designed and synthesized to combine fragments commonly found in allosteric AMPK activators and AT

Topics: AMP-Activated Protein Kinases; Animals; Benzimidazoles; Biphenyl Compounds; Cattle; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Enzyme Activators; Glycosylation; Hypoglycemic Agents; Lipopolysaccharides; Macrophages; Mice; Nitric Oxide; Serum Albumin, Bovine; Solubility; Structure-Activity Relationship

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. Using a homogeneous scintillation proximity assay (SPA), we identified a new small-molecule AMPK activator, ZLN024, which allosterically stimulated active AMPK heterotrimers and the inactive α1 subunit truncations α1 (1-394) and α1 (1-335) but not α1 (1-312). AMPK activation by ZLN024 requires the pre-phosphorylation of Thr-172 by at least one upstream kinase and protects AMPK Thr-172 against dephosphorylation by PP2Cα. ZLN024 activated AMPK in L6 myotubes and stimulated glucose uptake and fatty acid oxidation without increasing the ADP/ATP ratio. ZLN024 also activated AMPK in primary hepatocytes, decreased fatty acid synthesis and glucose output. Treatment of db/db mice with 15 mg/kg/day ZLN024 improved glucose tolerance; liver tissue weight, triacylglycerol and the total cholesterol content were decreased. The hepatic transcriptional level of G6Pase, FAS and mtGPAT were reduced. The transcription of genes involved in fatty acid oxidation and the mitochondrial biogenesis of muscle tissue were elevated. The ACC phosphorylation was increased in muscle and liver. This study provides a novel allosteric AMPK activator for functional study in vitro and in vivo and demonstrates that AMPK allosteric activators could be a promising therapeutic approach for type 2 diabetes mellitus and metabolic syndrome.

Topics: Adenosine Triphosphate; Adenylate Kinase; Allosteric Regulation; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Enzyme Activators; Fatty Acids; Glucose; HeLa Cells; Hepatocytes; Humans; Hypoglycemic Agents; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle Fibers, Skeletal; Phosphoprotein Phosphatases; Phosphorylation; Primary Cell Culture; Protein Phosphatase 2C; Protein Processing, Post-Translational; Pyrimidines; Rats