Journal article

Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release

John W Scott, Sandra Galic, Kate L Graham, Richard Foitzik, Naomi XY Ling, Toby A Dite, Samah MA Issa, Chris G Langendorf, Qing Ping Weng, Helen E Thomas, Thomas W Kay, Neal C Birnberg, Gregory R Steinberg, Bruce E Kemp, Jonathan S Oakhill



The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis. Pharmacological inhibition of AMPK is regarded as a therapeutic strategy in some disease settings including obesity and cancer; however, the broadly used direct AMPK inhibitor compound C suffers from poor selectivity. We have discovered a dihydroxyquinoline drug (MT47-100) with novel AMPK regulatory properties, being simultaneously a direct activator and inhibitor of AMPK complexes containing the β1 or β2 isoform, respectively. Allosteric inhibition by MT47-100 was dependent on the β2 carbohydrate-binding module (CBM) and determined by three non-conserved CBM residues (I..

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