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. Reprint(PDF)
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)
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)
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)