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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/E1142    most recent 90298.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cho, H. Articles by Briscoe, C. P. Search for Related Content PubMed PubMed Citation Articles by Cho, H. Articles by Briscoe, C. P.

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

¹Diabetes Biology Department, ²Biochemical Pharmacology and ³Structural Biology, Pfizer Incorporated, San Diego, California; and ⁴Division of Cardiovascular, Metabolic and Endocrine Diseases, Pfizer Incorporated, Groton, Conneticut

Submitted 17 March 2008 ; accepted in final form 25 August 2008

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. Compound A dosed at 30 mg/kg for 13 days in high-fat fed mice resulted in a significant decrease in phosphorylated c-Jun in adipose tissue accompanied by a decrease in weight and reductions in glucose and triglycerides and increases in insulin sensitivity to levels comparable with those in lean control mice. The ability of compound A to reduce the insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) von Ser307 and partially reverse the free fatty acid inhibition of glucose uptake in 3T3L1 adipocytes, suggests that enhancement of insulin signaling in addition to weight loss may contribute to the effects of compound A on insulin sensitization in vivo. Pharmacological inhibition of JNK using compound A may therefore offer an effective therapy for type 2 diabetes mediated at least in part via weight reduction.

Jun NH₂-terminal kinase; insulin sensitizer; weight loss; diet-induced obese mice