| MECHANISM OF ACTION |
inhibits p38 mitogen-activated protein (MAP) kinase by binding to a novel allosteric binding pocket on the enzyme.
p38 MAP kinase plays a critical role in regulating the production of several proinflammatory cytokines, such as tumor necrosis factor- (TNF-) and interleukin-1beta. Overproduction of these cytokines is associated with various inflammatory conditions. BIRB 796 had higher binding affinity than the lead compounds and inhibited p38 MAP kinase activity in cell culture at low-nanomolar levels.
The mechanism of BIRB 796 is unique. In the presence of the drug, the enzyme undergoes a large conformational change that exposes an allosteric binding pocket to which BIRB 796 binds. In the initial conformation, called "DFG-in," a key aspartate phenylalanine-glycine (DFG) motif in the enzyme active site allows binding of adenosine triphosphate (ATP). In the changed conformation, "DFG-out," BIRB 796 is bound to the exposed allosteric pocket, and ATP can no longer bind, thus blocking enzyme activity. This type of conformational change had not been observed previously for any serine-threonine protein kinase, the class of enzyme to which p38 MAP kinase belongs. See Lit. Ref.
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