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

1998; Elsevier BV; Volume: 8; Issue: 20 Linguagem: Inglês

10.1016/s0960-894x(98)00522-8

1464-3405

John V. Duncia, Joseph B. Santella, C. Anne Higley, William J. Pitts, John Wityak, William E. Frietze, F. Wayne Rankin, Jung-Hui Sun, Richard A. Earl, A. Christine Tabaka, Christopher A. Teleha, Karl F. Blom, Margaret Favata, Elizabeth J. Manos, Andrea J. Daulerio, Deborah A. Stradley, Kurumi Y. Horiuchi, Robert A. Copeland, Peggy Scherle, James M. Trzăskos, Ronald L. Magolda, George L. Trainor, Ruth R. Wexler, Frank W. Hobbs, Richard E. Olson,

Protein Kinase Regulation and GTPase Signaling

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 activity than parent, U0126.