Bisbubstrate inhibitors of kinases

Details Bisbubstrate inhibitors of kinases Bisbubstrate inhibitors of kinases

2006-05-16

2006-05-16

Steadman, David J. (Department: 1656)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C530S303000, C530S326000

Reexamination Certificate

active

07045617

ABSTRACT:
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.

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