Non-specific in vivo inhibition of CK1 by the pyridinyl imidazole p38 inhibitors SB 203580 and SB 202190

• Published in: BMB reports 2009-03, Vol.42 (3), p.142-147
• Main Authors: Shanware, Naval P. (The University of Wisconsin-Madison Medical School, WI, Madison, USA), Williams, Leah M. (The University of Wisconsin-Madison Medical School, WI, Madison, USA), Bowler, Michael J. (The University of Wisconsin-Madison Medical School, WI, Madison, USA), Tibbetts, Randal S. (The University of Wisconsin-Madison Medical School, WI, Madison, USA), E-mail: [e-mail]
• Format: Article
• Language: English
• Subjects: Casein kinase; Casein Kinase I - antagonists & inhibitors; Cell Line; CICLOHEXIMIDA; CK1; CK2; CREB; Cyclic AMP Response Element-Binding Protein - metabolism; CYCLOHEXIMIDE; Humans; Imidazoles - pharmacology; Non-specific; p38; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Phosphorylation - drug effects; Phosphoserine - metabolism; Protein Biosynthesis - drug effects; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; SB202190; SB203580; Stress, Physiological - drug effects; Stress-activated protein kinase; Substrate Specificity - drug effects; Suppression, Genetic - drug effects
• ISSN: 1976-6696; 1976-670X
• DOI: 10.5483/bmbrep.2009.42.3.142

Small-molecule inhibitors of protein kinases have contributed immensely to our understanding of biological signaling pathways and have been exploited therapeutically for the treatment of cancers and other disease states. The pyridinyl imidazole compounds SB 203580 and SB 202190 were identified as ATP competitive antagonists of the p38 stress-activated protein kinases and have been widely used to elucidate p38-dependent cellular processes. Here, we identify S8 203580 and SB 202190 as potent inhibitors of stress-induced CREB phosphorylation on Serine 111 (Ser-111) in intact cells. Unexpectedly, we found that the inhibitory activity of SB 203580 and SB 202190 on CREB phosphorylation was independent of p38, but instead correlated with inhibition of casein kinase 1 (CK1) in vitro. The inhibition of CK1-mediated CREB phosphorylation by concentrations of pyridinyl imidazoles commonly employed to suppress p38, suggests that in some cases conclusions of p38-dependence derived solely from the use of these inhibitors may be invalid.