公开(公告)号：US07045617B2

公开(公告)日：2006-05-16

申请号：US09811870

申请日：2001-03-21

申请人： Philip A. Cole ,  Keykavous Parang ,  Ararat Abloogu ,  Ronald A. Kohanski ,  Aliya Courtney

发明人： Philip A. Cole ,  Keykavous Parang ,  Ararat Abloogu ,  Ronald A. Kohanski ,  Aliya Courtney

IPC分类号： C07H19/20 ,  A61K38/28 ,  A61K38/00 ,  A61K38/04

CPC分类号： A61K47/62

摘要： Protein kinase inhibitors have applications as anti-cancer therapeutic agents and biological tools in cell signalling. Potent and selective bisubstrate inhibitors for the insulin receptor tyrosine kinase are based on a phosphoryl transfer mechanism involving a dissociative transition state. One such inhibitor is synthesized by linking ATPγS to a peptide substrate analog via a two-carbon spacer. The compound is a high-affinity competitive inhibitor against both nucleotide and peptide substrate and shows a slow off-rate. A crystal structure of this inhibitor bound to the tyrosine kinase domain of the insulin receptor confirms the key design features inspired by a dissociative transition state, and reveal that the linker takes part in the octahedral coordination of an active site Mg2+ ion.

摘要翻译： 蛋白激酶抑制剂可用作细胞信号传导中的抗癌治疗剂和生物工具。 用于胰岛素受体酪氨酸激酶的强效选择性双底物抑制剂是基于涉及离解过渡态的磷酰转移机制。 一种这样的抑制剂通过经由二碳间隔基连接ATPgammaS到肽底物类似物来合成。 该化合物是针对核苷酸和肽底物的高亲和力竞争性抑制剂，显示出缓慢的脱离率。 结合胰岛素受体的酪氨酸激酶结构域的这种抑制剂的晶体结构证实了由解离过渡状态启发的关键设计特征，并且揭示了连接体参与活性位点Mg 2+的八面体配位， / SUP>离子。