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 journalArticle

Abstract

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
Volume8
Issue number1
DOIs
StatePublished - 2001

Fingerprint

Protein Kinase Inhibitors
Cell signaling
Peptides
Insulin Receptor
Substrates
Antineoplastic Agents
Protein-Tyrosine Kinases
Catalytic Domain
Carbon
Nucleotides
Crystal structure
insulin receptor tyrosine kinase
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Genetics

Cite this

Parang, K., Till, J. H., Ablooglu, A. J., Kohanski, R. A., Hubbard, S. R., & Cole, P. A. (2001). Mechanism-based design of a protein kinase inhibitor. Nature Structural Biology, 8(1), 37-41. https://doi.org/10.1038/83028

Mechanism-based design of a protein kinase inhibitor. / Parang, Keykavous; Till, Jeffrey H.; Ablooglu, Ararat J.; Kohanski, Ronald A.; Hubbard, Stevan R.; Cole, Philip A.

In: Nature Structural Biology, Vol. 8, No. 1, 2001, p. 37-41.

Research output: Contribution to journalArticle

Parang, K, Till, JH, Ablooglu, AJ, Kohanski, RA, Hubbard, SR & Cole, PA 2001, 'Mechanism-based design of a protein kinase inhibitor', Nature Structural Biology, vol. 8, no. 1, pp. 37-41. https://doi.org/10.1038/83028
Parang K, Till JH, Ablooglu AJ, Kohanski RA, Hubbard SR, Cole PA. Mechanism-based design of a protein kinase inhibitor. Nature Structural Biology. 2001;8(1):37-41. https://doi.org/10.1038/83028
Parang, Keykavous ; Till, Jeffrey H. ; Ablooglu, Ararat J. ; Kohanski, Ronald A. ; Hubbard, Stevan R. ; Cole, Philip A. / Mechanism-based design of a protein kinase inhibitor. In: Nature Structural Biology. 2001 ; Vol. 8, No. 1. pp. 37-41.
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