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

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• 作者：Yu Mi Ahn ; Michael Clare ; Carol L. Ensinger ; Molly M. Hood ; John W. Lord ; Wei-Ping Lu ; David F. Miller ; William C. Patt ; Bryan D. Smith ; Lakshminarayana Vogeti ; Michael D. Kaufman ; Peter A. Petillo ; S
• 关键词：p38 kinase inhibitor ; Type II kinase inhibitor ; Switch contol inhibitor ; MAP kinase inhibitor ; Arthritis
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：1 October 2010
• 年：2010
• 卷：20
• 期：19
• 页码：5793-5798
• 全文大小：1535 K

文摘

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.