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
  • 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.