Pharmacological characterization of a small-molecule inhibitor of c-Jun kinase

c-Jun NH2-terminal kinase (JNK) plays an important role in insulin resistance; however, identification of pharmacologically potent and selective small molecule JNK inhibitors has been limited. Compound A has a cell IC50 of 102 nM and is at least 100-fold selective against related kinases and 27-fold selective against glycogen synthase kinase-3β and cyclin-dependent kinase-2. In C57BL/6 mice, compound A reduced LPS-mediated increases in both plasma cytokine levels and phosphorylated c-Jun in adipose tissue. Treatment of mice fed a high-fat diet with compound A for 3 wk resulted in a 13.1 ± 1% decrease in body weight and a 9.3 ± 1.5% decrease in body fat, compared with a 6.6 ± 2.1% increase in body weight and a 6.7 ± 2.1% increase in body fat in vehicle-treated mice. Mice pair fed to those that received compound A exhibited a body weight decrease of 7 ± 1% and a decrease in body fat of 1.6 ± 1.3%, suggesting that reductions in food intake could not account solely for the reductions in adiposity observed. Co...