MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products

…, JB Santella, CA Higley, WJ Pitts, J Wityak…

Index: Duncia, John V.; Santella III, Joseph B.; Higley, C. Anne; Pitts, William J.; Wityak, John; Frietze, William E.; Rankin, F. Wayne; Sun, Jung-Hui; Earl, Richard A.; Tabaka, A. Christine; Teleha, Christopher A.; Blom, Karl F.; Favata, Margaret F.; Manos, Elizabeth J.; Daulerio, Andrea J.; Stradley, Deborah A.; Horiuchi, Kurumi; Copeland, Robert A.; Scherle, Peggy A.; Trzaskos, James M.; Magolda, Ronald L.; Trainor, George L.; Wexler, Ruth R.; Hobbs, Frank W.; Olson, Richard E. Bioorganic and Medicinal Chemistry Letters, 1998 , vol. 8, # 20 p. 2839 - 2844

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Citation Number: 366

Abstract

In search of antiinflammatory drugs with a new mechanism of action, U0126 was found to functionally antagonize AP-1 transcriptional activity via noncompetitive inhibition of the dual specificity kinase MEK with an IC50 of 0.07 μM for MEK 1 and 0.06 μM for MEK 2. U0126 can undergo isomerization and cyclization reactions to form a variety of products, both chemically and in vivo, all of which exhibit less affinity for MEK and lower inhibition of AP-1 ...