Design, synthesis, and characterization of an ATP-peptide conjugate inhibitor of protein kinase A

Aliya C. Hines; Philip A. Cole

doi:10.1016/j.bmcl.2004.03.039

Design, synthesis, and characterization of an ATP-peptide conjugate inhibitor of protein kinase A

Aliya C. Hines, Philip A. Cole

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

An ATP-peptide conjugate was synthesized as a bisubstrate analogue inhibitor of the serine/threonine kinase protein kinase A. The compound was found to be a linear, competitive inhibitor with respect to ATP substrate, exhibiting a K_i of 3.8μM. The compound was noncompetitive with respect to peptide substrate. The inhibitor was shown to be selective for protein kinase A versus the closely related protein kinase C as well as tyrosine kinase Csk. This analysis provides new evidence for the dissociative transition state of protein serine/threonine kinases and illustrates a simple method to convert a low affinity peptide substrate to a selective and moderately potent inhibitor for these enzymes.

Original language	English (US)
Pages (from-to)	2951-2954
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	14
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2004.03.039
State	Published - Jun 7 2004
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2004.03.039

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abstract = "An ATP-peptide conjugate was synthesized as a bisubstrate analogue inhibitor of the serine/threonine kinase protein kinase A. The compound was found to be a linear, competitive inhibitor with respect to ATP substrate, exhibiting a Ki of 3.8μM. The compound was noncompetitive with respect to peptide substrate. The inhibitor was shown to be selective for protein kinase A versus the closely related protein kinase C as well as tyrosine kinase Csk. This analysis provides new evidence for the dissociative transition state of protein serine/threonine kinases and illustrates a simple method to convert a low affinity peptide substrate to a selective and moderately potent inhibitor for these enzymes.",

author = "Hines, {Aliya C.} and Cole, {Philip A.}",

note = "Funding Information: We acknowledge the David and Lucille Packard Foundation and the UNCF/Merck Graduate Science Initiative (A.C.H.) and the NIH (P.A.C.) for financial support. We also thank K. Parang and members of the Cole laboratory for helpful suggestions and discussions.",

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AU - Hines, Aliya C.

AU - Cole, Philip A.

N1 - Funding Information: We acknowledge the David and Lucille Packard Foundation and the UNCF/Merck Graduate Science Initiative (A.C.H.) and the NIH (P.A.C.) for financial support. We also thank K. Parang and members of the Cole laboratory for helpful suggestions and discussions.

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AB - An ATP-peptide conjugate was synthesized as a bisubstrate analogue inhibitor of the serine/threonine kinase protein kinase A. The compound was found to be a linear, competitive inhibitor with respect to ATP substrate, exhibiting a Ki of 3.8μM. The compound was noncompetitive with respect to peptide substrate. The inhibitor was shown to be selective for protein kinase A versus the closely related protein kinase C as well as tyrosine kinase Csk. This analysis provides new evidence for the dissociative transition state of protein serine/threonine kinases and illustrates a simple method to convert a low affinity peptide substrate to a selective and moderately potent inhibitor for these enzymes.

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Design, synthesis, and characterization of an ATP-peptide conjugate inhibitor of protein kinase A

Abstract

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