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

American Journal of Physiology. Endocrinology and Metabolism
Helen ChoCelia P Briscoe

Abstract

c-Jun NH(2)-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 IC(50) of 102 nM and is at least 100-fold selective against related kinases and 27-fold selective against glycogen synthase kinase-3beta 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 trigl...Continue Reading

References

Dec 1, 1994·Molecular and Cellular Biology·H K SlussR J Davis
Nov 22, 2001·Proceedings of the National Academy of Sciences of the United States of America·B L BennettD W Anderson
Nov 6, 2002·The Journal of Biological Chemistry·Yong Hee LeeMorris F White
Nov 26, 2002·Nature·Jiro HirosumiGökhan S Hotamisligil
Jan 22, 2003·The Biochemical Journal·Jenny BainPhilip Cohen
Sep 28, 2004·Nature Medicine·Hideaki KanetoMasatsugu Hori
May 3, 2005·The Journal of Clinical Investigation·Kathryn E Wellen, Gökhan S Hotamisligil
Jul 5, 2006·Proceedings of the National Academy of Sciences of the United States of America·Gürol TuncmanGökhan S Hotamisligil
Sep 2, 2006·The European Respiratory Journal·B L Bennett
Oct 20, 2006·Proceedings of the National Academy of Sciences of the United States of America·Giovanni SolinasMichael Karin
Jul 31, 2007·Biochemical and Biophysical Research Communications·Celia P BriscoeB Ganesh Bhat

❮ Previous
Next ❯

Citations

Dec 3, 2010·Science Translational Medicine·Sara N Vallerie, Gökhan S Hotamisligil
Oct 12, 2011·World Journal of Gastroenterology : WJG·Giovanni Tarantino, Armando Caputi
Jun 3, 2014·BMC Genomics·Silvia von der HeydeBernhard G Baumgartner
Oct 11, 2012·Journal of Biomedicine & Biotechnology·Sandro M HirabaraRui Curi
Nov 29, 2011·Journal of Hepatology·Beicheng Sun, Michael Karin
Nov 11, 2009·Biochimica Et Biophysica Acta·Marie A BogoyevitchDominic C H Ng
Jan 23, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·Rosa Bretón-RomeroNaomi M Hamburg
May 29, 2009·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Ulla C KoppTomas Hökfelt
Feb 16, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Thais de Castro BarbosaJuleen R Zierath
May 15, 2013·Annals of Medicine·Giovanni Tarantino, Domenico Capone
Mar 13, 2015·Biomedit︠s︡inskai︠a︡ khimii︠a︡·L S LitvinovaN S Fattakhov
Sep 4, 2015·World Journal of Hepatology·Fauzia Z KhanAijaz Ahmed

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.