Bioorganic & medicinal chemistry letters, 2010-10, Vol.20 (19), p.5793-5798
2010
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Details
- Autor(en) / Beteiligte
- Titel
- Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region
- Ist Teil von
- Bioorganic & medicinal chemistry letters, 2010-10, Vol.20 (19), p.5793-5798
- Ort / Verlag
- Amsterdam: Elsevier Ltd
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Switch control pocket inhibitors of p38- alpha kinase are described. X-ray crystallography reveals a unique mode of binding to the switch control pocket residues arginine 67 or arginine 70. Switch control pocket inhibitors of p38- alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38- alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38- alpha kinase.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0960-894XeISSN: 1464-3405DOI: 10.1016/j.bmcl.2010.07.134Titel-ID: cdi_proquest_miscellaneous_754004552
- Format
- –
- Schlagworte
- Adenosine Triphosphate - chemistry, Arthritis, Binding Sites, Biological and medical sciences, Bones, joints and connective tissue. Antiinflammatory agents, Computer Simulation, Crystallography, X-Ray, HeLa Cells, Humans, Kinetics, MAP kinase inhibitor, Medical sciences, Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors, Mitogen-Activated Protein Kinase 14 - metabolism, p38 kinase inhibitor, Pharmacology. Drug treatments, Phenylurea Compounds - chemical synthesis, Phenylurea Compounds - chemistry, Phenylurea Compounds - pharmacology, Phosphorylation, Protein Binding, Protein Kinase Inhibitors - chemical synthesis, Protein Kinase Inhibitors - chemistry, Protein Kinase Inhibitors - pharmacology, Pyrazoles - chemical synthesis, Pyrazoles - chemistry, Pyrazoles - pharmacology, Structure-Activity Relationship, Switch contol inhibitor, Type II kinase inhibitor