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Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site

Nature Structural Biology volume 9, pages 268–272 (2002)Cite this article

Abstract

The p38 MAP kinase plays a crucial role in regulating the production of proinflammatory cytokines, such as tumor necrosis factor and interleukin-1. Blocking this kinase may offer an effective therapy for treating many inflammatory diseases. Here we report a new allosteric binding site for a diaryl urea class of highly potent and selective inhibitors against human p38 MAP kinase. The formation of this binding site requires a large conformational change not observed previously for any of the protein Ser/Thr kinases. This change is in the highly conserved Asp-Phe-Gly motif within the active site of the kinase. Solution studies demonstrate that this class of compounds has slow binding kinetics, consistent with the requirement for conformational change. Improving interactions in this allosteric pocket, as well as establishing binding interactions in the ATP pocket, enhanced the affinity of the inhibitors by 12,000-fold. One of the most potent compounds in this series, BIRB 796, has picomolar affinity for the kinase and low nanomolar inhibitory activity in cell culture.

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Figure 1: In vitro and in vivo data for selected p38 inhibitors.
Figure 2: A new allosteric binding pocket for compound 1 in human p38 MAP kinase.
Figure 3: A conformational change in the kinase is required for the binding of diaryl urea inhibitors.
Figure 4: Kinetics of compound binding to p38 MAP kinase.

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Acknowledgements

We are indebted to the following people: J. Pelletier, A. Proto and M. Basso for assistance with biological assays; A. Swinamer, B. Klaus and M. Moriak for the preparation of various analogs of BIRB 796; M. Morelock for statistical analysis; L. Rondano for graphics support; and R. Winquist and P. Farina for useful discussions. We acknowledge Glaxo SmithKline Pharmaceuticals for the generous gift of SK&F 86002.

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Authors and Affiliations

  1. Department of Biology, Boehringer Ingelheim Pharmaceuticals, Research and Development Center, 900 Ridgebury Road, Ridgefield, 06877, Connecticut, USA

    Christopher Pargellis, Laurie Churchill, Anne G. Graham, Peter M. Grob & Susan Pav

  2. Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Research and Development Center, 900 Ridgebury Road, Ridgefield, 06877, Connecticut, USA

    Liang Tong, Pier F. Cirillo, Thomas Gilmore, Eugene R. Hickey, Neil Moss & John Regan

  3. Department of Biological Sciences, Columbia University, New York, 10027, New York, USA

    Liang Tong

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  1. Christopher Pargellis
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Correspondence to Christopher Pargellis or Liang Tong.

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Pargellis, C., Tong, L., Churchill, L. et al. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Mol Biol 9, 268–272 (2002). https://doi.org/10.1038/nsb770

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