INHIBITION OF PYRUVATE-DEHYDROGENASE KINASE BY HALOGENATED ACETOPHENONES

The activity of pyruvate dehydrogenase (PDH), and hence of glucose oxi dation, is regulated by reversible phosphorylation. We have searched f or novel PDH-Kinase inhibitors using a high-throughput microtiter plat e assay. A series of halogenated acetophenones with potent activity ag ainst PDH-Kinase (IC50 = 1-3 mu M) and inactive towards other protein kinases was identified. The lead compound displayed non-linear kinetic s and was shown to be an uncompetitive inhibitor with respect to ATP. These novel inhibitors of PDH-Kinase may be potential new drug leads f or the treatment of diabetes or ischaemic conditions. (C) 1995 Wiley-L iss, Inc.