The p38 MAP Kinase Project
The p38 MAP kinase is activated in response to cellular stress, such as
stimulation by LPS. A series of compounds, known as pyridinyl-imidazoles,
can inhibit the p38-mediated production of pro-inflammatory cytokines (TNF
and IL-1) in response to LPS stimulation. These compounds are highly
specific against the p38 MAP kinase.
Major findings from this project
- The pyridinyl-imidazole inhibitors bind in the ATP pocket,
and is therefore competitive against ATP.
- The specificity of this series of compounds is determined by
the presence of the 4-phenyl ring, which occupies a binding pocket
in the kinase that is not utilized by ATP.
- A threonine residue in p38 MAP kinase is crucial for the
presence of this pocket. In most other kinases, this residue is
replaced by larger Gln or Met residues. The T->Q or T->M single-point
mutants of p38 are insensitive to the inhibitors.
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A new, diaryl urea series of highly selective p38 MAP kinase inhibitors
has been developed.
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The compound BIRB796 has Ki of 0.1 nM, with a very slow off rate.
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The compound binds to an allosteric pocket in p38, which is
revealed when the highly conserved DFG motif assumes a different
conformation (the DFG-out conformation).
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The compounds are not directly competitive with ATP binding. But
the DFG-out conformation is not compatible with ATP binding.
Publications from this project
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S. Pav, D. M. White, S. Rogers, K. M. Crane, C. L. Cywin, W. Davidson, J. Hopkins, M. L. Brown,
C. A. Pargellis & L. Tong. (1997). Crystallization and preliminary crystallographic analysis of
recombinant human p38 MAP kinase. Protein Science, 6, 242-245.
Reprint(PDF)
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L. Tong, S. Pav, D. M. White, S. Rogers, K. M. Crane, C. L. Cywin, M. L. Brown & C. A.
Pargellis. (1997). A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket.
Nature Struct. Biol. 4, 311-316.
Reprint(PDF)
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C. Pargellis, L. Tong, L. Churchill, P.F. Cirillo, T. Gilmore, A.G. Graham, P.M. Grob, E.R. Hickey,
N. Moss, S. Pav & J. Regan. (2002). Inhibition of p38 MAP kinase by utilizing a novel allosteric
binding site. Nature Struct. Biol. 9, 268-272.
Reprint(PDF)
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J. Regan, S. Breitfelder, P. Cirillo, T. Gilmore, A.G. Graham, E. Hickey, B. Klaus, J. Madwed, M.
Moriak, N. Moss, C. Pargellis, S. Pav, A. Proto, A. Swanimer, L. Tong & C. Torcellini. (2002).
Pyrazole urea-based inhibitors of p38 MAP kinase: From lead compound to clinical candidate. J.
Med. Chem. 45, 2994-3008.
Reprint(PDF)
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