Allosteric FBPase inhibitors gain 10(5) times in potency when simultaneously binding two neighboring AMP sites.

Paul Hebeisen, Bernd Kuhn, Philipp Kohler, Marcel Gubler, Walter Huber, Eric Kitas, Brigitte Schott, Jörg Benz, Catherine Joseph, Armin Ruf

F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. paul.hebeisen@roche.com

Bioorganic & medicinal chemistry letters 2008 Aug 15

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Human fructose-1,6-bisphosphatase (FBPase, EC 3.1.3.11) is a key gluconeogenic enzyme, responsible for the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate, and thus presents an opportunity for the development of novel therapeutics focused on lowering the hepatic glucose production in type 2 diabetics. In its active form FBPase exists as a homotetramer and is allosterically regulated by AMP. In an HTS campaign aromatic sulfonylureas have been identified as FBPase inhibitors mimicking AMP. By bridging two adjacent allosteric binding sites using two aromatic sulfonylureas as anchor units and covalently linking them, it was possible to obtain dual binding AMP site inhibitors that exhibit a strong inhibitory effect.

Citation

Paul Hebeisen, Bernd Kuhn, Philipp Kohler, Marcel Gubler, Walter Huber, Eric Kitas, Brigitte Schott, Jörg Benz, Catherine Joseph, Armin Ruf. Allosteric FBPase inhibitors gain 10(5) times in potency when simultaneously binding two neighboring AMP sites. Bioorganic & medicinal chemistry letters. 2008 Aug 15;18(16):4708-12