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

Angell, R.M; Angell, T.D; Bamborough, P; Bamford, M.J; Chung, C-W; Cockerill, G.S; Flack, S.S; Jones, K.L; Laine, D.I; Longstaff, T; Ludbrook, S; Pearson, R; Smith, K.J; Smee, P.A; Somers, D.O; Walker, A.L

Authors

R.M Angell

T.D Angell

P Bamborough

M.J Bamford

C-W Chung

G.S Cockerill

S.S Flack

K.L Jones

D.I Laine

T Longstaff

S Ludbrook

R Pearson

K.J Smith

P.A Smee

D.O Somers

A.L Walker



Abstract

The biphenyl amides (BPAs) are a series of p38α 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 p38α 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.

Citation

Angell, R., Angell, T., Bamborough, P., Bamford, M., Chung, C., Cockerill, G., …Walker, A. (2008). Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes. Bioorganic and Medicinal Chemistry Letters, 18(15), 4433-4437. https://doi.org/10.1016/j.bmcl.2008.06.028

Journal Article Type Article
Publication Date Jan 1, 2008
Deposit Date Sep 27, 2013
Journal Bioorganic and Medicinal Chemistry Letters
Print ISSN 0960-894X
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 18
Issue 15
Pages 4433-4437
DOI https://doi.org/10.1016/j.bmcl.2008.06.028
Keywords p38 Kinase inhibitors, MAP kinase, biphenyl amide, protein kinase X-ray structure, binding mode, DFG-out, selectivity, kinetics

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