This novel ATP binding pocket-directed inhibitor (FW = 323.32 g/mol), systematically named 2-[(2,4-dihydroxyphenyl)sulfonyl]isoindoline-4,6- diol, targets all four PDK isoforms, with an IC50 = 0.8 μM and Ki = 0.24 μM for PDK2. Its design is based on structure-guided design, converting a known Hsp90 inhibitor into a series of highly specific PDK inhibitors, substituting a sulfonyl group in place of a carbonyl in the parent compound. This modification results in weak binding to Hsp90 (Ki = 47 μM). PS10 administration (70 mg/kg) to diet-induced obese mice significantly augments PDC activity with reduced phosphorylation in different tissues. Prolonged treatment improves glucose tolerance, with notably lessened hepatic steatosis in a mouse model. Such findings suggest pharmacological targeting of PDK may be useful in controlling glucose and fat levels in obesity and type 2 diabetes.
