2. Academic Validation
  3. Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes

Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes

  • Bioorg Med Chem Lett. 2008 Aug 1;18(15):4433-7. doi: 10.1016/j.bmcl.2008.06.028.
Richard M Angell 1,  Tony D Angell,  Paul Bamborough,  Mark J Bamford,  Chun-wa Chung,  Stuart G Cockerill,  Stephen S Flack,  Katherine L Jones,  Dramane I Laine,  Timothy Longstaff,  Steve Ludbrook,  Rosannah Pearson,  Kathryn J Smith,  Penny A Smee,  Don O Somers,  Ann L Walker
Affiliations

Affiliation

  • 1 GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
PMID: 18602262 DOI: 10.1016/j.bmcl.2008.06.028
Abstract

The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated Enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.

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