BIRB796 inhibits all p38 MAPK isoforms in vitro and in vivo

The compound BIRB796 inhibits the stress-activated protein kinases p38 alpha and p38 beta and is undergoing clinical trials for the treatment of inflammatory diseases. Here we report that BIRB796 also inhibits the activity and the activation of SAPK3/p38 gamma. This occurs at higher concentrations of BIRB796 than those that inhibit p38 alpha and p38 alpha and at lower concentrations than those that inhibit the activation of JNK isoforms. We also show that at these concentrations, BIRB796 blocks the stress-induced phosphorylation of the scaffold protein SAP97, further establishing that this is a physiological substrate of SAPK3/p38 gamma. Our results demonstrate that BIRB796, in combination with SB203580, a compound that inhibits p38 alpha and p38 beta, but not the other p38 isoforms, can be used to identify physiological substrates of SAPK3/p38 gamma as well as those of p38 alpha and p38 beta.