SB-203580 IS A SPECIFIC INHIBITOR OF A MAP KINASE HOMOLOG WHICH IS STIMULATED BY CELLULAR STRESSES AND INTERLEUKIN-1

A class of pyridinyl imidazoles inhibit the MAP kinase homologue, term ed here reactivating kinase (RK) [Lee et al, (1994) Nature 372, 739-74 6]. We now show that one of these compounds (SE 203580) inhibits RK in vitro (IC50 = 0.6 mu M), suppresses the activation of MAPKAP kinase-2 and prevents the phosphorylation of heat shock protein (HSP) 27 in re sponse to interleukin-1, cellular stresses and bacterial endotoxin in vivo. These results establish that MAPKAP kinase-2 is a physiological RK substrate, and that HSP27 is phosphorylated by MAPKAP kinase-2 in v ivo. The specificity of SB 203580 was indicated by its failure to inhi bit 12 other protein kinases in vitro, and by its lack of effect on th e activation of RK kinase and other MAP kinase cascades in vivo. We su ggest that SE 203580 will be useful for identifying other physiologica l roles and targets of RK and MAPKAP kinase-2.