Portal de Periódicos da CAPES

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

2010; Elsevier BV; Volume: 20; Issue: 19 Linguagem: Inglês

10.1016/j.bmcl.2010.07.134

1464-3405

Yu Mi Ahn, Michael Clare, Carol L. Ensinger, Molly M. Hood, John Lord, Wei-Ping Lu, David F. Miller, William C. Patt, Bryan D. Smith, Lakshminarayana Vogeti, Michael D. Kaufman, Peter A. Petillo, Scott Wise, Jan Abendroth, Lawrence Chun, Robin Clark, M.D. Feese, Hidong Kim, Lance Stewart, Daniel L. Flynn,

Cancer Mechanisms and Therapy

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.