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 transistion state. One such inhibitor is synthesized by linking ATP gamma S 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<2+> ion.
申请公布号
WO0170770(A3)
申请公布日期
2002.07.04
申请号
WO2001US08886
申请日期
2001.03.21
申请人
THE JOHNS HOPKINS UNIVERSITY;COURTNEY, ALIYA;COLE, PHILIP, A.;PARANG, KEYKAVOUS;ABLOOGU, ARARAT;KOHANSKI, RON
发明人
COURTNEY, ALIYA;COLE, PHILIP, A.;PARANG, KEYKAVOUS;ABLOOGU, ARARAT;KOHANSKI, RON