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.
A new, diaryl urea series of highly selective p38 MAP kinase inhibitors
has been developed.
The compound BIRB796 has Ki of 0.1 nM, with a very slow off rate.
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).
The compounds are not directly competitive with ATP binding. But
the DFG-out conformation is not compatible with ATP binding.
Publications from this project
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.
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.
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.
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.
© copyright 2000-2017, Liang Tong.