Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 19; pp. 5793 - 5798
• Main Authors: Ahn, Yu Mi, Clare, Michael, Ensinger, Carol L., Hood, Molly M., Lord, John W., Lu, Wei-Ping, Miller, David F., Patt, William C., Smith, Bryan D., Vogeti, Lakshminarayana, Kaufman, Michael D., Petillo, Peter A., Wise, Scott C., Abendroth, Jan, Chun, Lawrence, Clark, Robin, Feese, Michael, Kim, Hidong, Stewart, Lance, Flynn, Daniel L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.10.2010; Elsevier
• Subjects: 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; p38 kinase inhibitor; Arthritis; Switch contol inhibitor; Type II kinase inhibitor; MAP kinase inhibitor; Rat; Binding site; Modeling; Structure activity relation; Chlorine Organic compounds; Molecular model; Pyrazole derivatives; Ureas; Tumor necrosis factor α; Enzyme; Transferases; Rodentia; Cytokine; Enzyme inhibitor; Mitogen-activated protein kinase; In vivo; Vertebrata; Mammalia; Animal; Carboxamide; Conformation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.07.134

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.