Discovery and Optimizationof 4,5-Diarylisoxazolesas Potent Dual Inhibitors of Pyruvate Dehydrogenase Kinase and HeatShock Protein 90.

Upregulation of pyruvate dehydrogenasekinase (PDHK) has been observedin a variety of cancers. Inhibition of PDHK offers an attractive opportunityfor the development of novel cancer therapies. To obtain novel PDHKinhibitors, we took advantage of the homology of the ATP-binding pocketbetween Heat Shock Protein 90 (HSP90) and PDHK, and utilized 4,5-diarylisoxazolebased HSP90 inhibitor for structural design. Our efforts led to theidentification of 5kthat inhibited PDHK1 with an IC50value of 17 nM, which, however, showed marginal cellularactivity. Further structural optimization resulted in compound 11awith improved cellular activity which could effectivelymodulate the metabolic profile of cancer cells and lead to the inhibitionof cancer cell proliferation, evidenced by the increased oxidativephosphorylation and decreased glycolysis and associated oxidativestress. Our results suggested 11aas an excellent leadcompound and a favorable biological tool to further evaluate the therapeuticpotential of PDHK and HSP90 dual inhibitors in the treatment of cancer. [ABSTRACT FROM AUTHOR]