Utility and Limitations of SP600125, an Inhibitor of Stress-Responsive c-Jun N-Terminal Kinase

Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) belongs to the mitogen-activated protein kinase (MAPK) family and plays an important role in many biological contexts. JNK is deeply involved in several serious human disorders, including inflammation, obesity, diabetes, neuronal disease and cancer. Accordingly, JNK has been recognized as an appropriate target for the treatment of these diseases, and much effort has been expended over the past 15 years to isolate JNK inhibitors that can inactivate this kinase. In 2001, the compound SP600125 was reported as the first JNK-specific inhibitor. Many researchers have subsequently employed SP600125 in in vitro and in vivo models to evaluate whether certain disease-associated events are JNK-dependent. Indeed, more than 1300 studies citing the use of SP600125 as a JNK inhibitor in cell cultures and animal models have been reported. However, although SP600125 has been employed successfully to inhibit JNK in several situations, there have been questions about its specificity for JNK. SP600125 can bind to a broad range of protein kinases and inhibit some of them with similar or greater potency than JNK, confirming that many additional kinases may be targets of SP600125. In this article, we review both the usefulness of SP60125 as a JNK inhibitor and the limitations to its specificity.