发明名称 |
Bisbubstrate inhibitors of kinases |
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 ATPgammaS 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 Mg<SUP>2+</SUP> ion.
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申请公布号 |
US7045617(B2) |
申请公布日期 |
2006.05.16 |
申请号 |
US20010811870 |
申请日期 |
2001.03.21 |
申请人 |
JOHNS HOPKINS UNIVERSITY |
发明人 |
COLE PHILIP A.;PARANG KEYKAVOUS;ABLOOGU ARARAT;KOHANSKI RONALD A.;COURTNEY ALIYA |
分类号 |
C07H19/20;A61K38/00;A61K38/04;A61K38/28;A61K47/48 |
主分类号 |
C07H19/20 |
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地址 |
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