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Mechanism-based design of a protein kinase inhibitor

Nature Structural Biology volume 8, pages 37–41 (2001)Cite this article

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.

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Figure 1: Synthetic compounds and mechanistic schemes.
Figure 2: Kinetic analysis of the inhibition of IRK by bisubstrate analog compound 2.
Figure 3: Crystal structure of the binary complex between cIRK and the bisubstrate inhibitor.

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Acknowledgements

We gratefully acknowledge support from the NIH (to R.A.K., S.R.H. and P.A.C.), and the Burroughs Wellcome Fund. We thank A. Mildvan for helpful discussions and critical reading of the manuscript. X-ray equipment at The Skirball Institute is partially supported by grants from The Kresge Foundation and The Hyde and Watson Foundation.

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Author notes

  1. Keykavous Parang, Jeffrey H. Till, Ararat J. Ablooglu and Ronald A. Kohanski: These authors contributed equally.

Authors and Affiliations

  1. Department of Pharmacology Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland , USA

    Keykavous Parang & Philip A. Cole

  2. Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, New York, 10016, USA

    Jeffrey H. Till & Stevan R. Hubbard

  3. Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Ararat J. Ablooglu & Ronald A. Kohanski

Authors
  1. Keykavous Parang
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  2. Jeffrey H. Till
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  3. Ararat J. Ablooglu
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  4. Ronald A. Kohanski
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  5. Stevan R. Hubbard
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  6. Philip A. Cole
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Corresponding authors

Correspondence to Stevan R. Hubbard or Philip A. Cole.

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Parang, K., Till, J., Ablooglu, A. et al. Mechanism-based design of a protein kinase inhibitor. Nat Struct Mol Biol 8, 37–41 (2001). https://doi.org/10.1038/83028

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