Mechanism-based design of a protein kinase inhibitor

Keykavous Parang, Jeffrey H. Till, Ararat J. Ablooglu, Ronald A. Kohanski, Stevan R. Hubbard, Philip A. Cole

Research output: Contribution to journalArticlepeer-review


Protein kinase inhibitors have applications as anticancer therapeutic agents and biological tools in cell signaling. Based on a phosphoryl transfer mechanism involving a dissociative transition state, a potent and selective bisubstrate inhibitor for the insulin receptor tyrosine kinase was synthesized by linking ATPγS to a peptide substrate analog via a two-carbon spacer. The compound was a high affinity competitive inhibitor against both nucleotide and peptide substrates and showed a slow off-rate. A crystal structure of this inhibitor bound to the tyrosine kinase domain of the insulin receptor confirmed the key design features inspired by a dissociative transition state, and revealed that the linker takes part in the octahedral coordination of an active site Mg2+. These studies suggest a general strategy for the development of selective protein kinase inhibitors.

Original languageEnglish (US)
Pages (from-to)37-41
Number of pages5
JournalNature Structural Biology
Issue number1
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics


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