Targeted Degradation of Protein Kinase A via a Stapled Peptide PROTAC

Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that bind and recruit an E3 ubiquitin ligase to a targeted protein of interest, often through the utilization of a small molecule inhibitor. To expand the possible range of kinase targets that can be degraded by PROTACs, we sought t...

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Bibliographic Details
Published in:	ACS chemical biology Vol. 19; no. 9; pp. 1888 - 1895
Main Authors:	Whittaker, Matthew K., Bendzunas, George N., Shirani, Mahsa, LeClair, Timothy J., Shebl, Bassem, Dill, Taylor C., Coffino, Philip, Simon, Sanford M., Kennedy, Eileen J.
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 20-09-2024
Subjects:	Cyclic AMP-Dependent Protein Kinases - metabolism Humans Letter Peptides - chemistry Peptides - metabolism Peptides - pharmacology Phosphorylation - drug effects Proteasome Endopeptidase Complex - metabolism Proteolysis - drug effects Ubiquitin-Protein Ligases - metabolism
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Summary:	Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that bind and recruit an E3 ubiquitin ligase to a targeted protein of interest, often through the utilization of a small molecule inhibitor. To expand the possible range of kinase targets that can be degraded by PROTACs, we sought to develop a PROTAC utilizing a hydrocarbon-stapled peptide as the targeting agent to bind the surface of a target protein of interest. In this study, we describe the development of a proteolysis-targeting chimera, dubbed Stapled Inhibitor Peptide - PROTAC or StIP-TAC, linking a hydrocarbon-stapled peptide with an E3 ligase ligand for targeted degradation of Protein Kinase A (PKA). This StIP-TAC molecule stimulated E3-mediated protein degradation of PKA, and this effect could be reversed by the addition of the proteasomal inhibitor MG-132. Further, StIP-TAC treatment led to a significant reduction in PKA substrate phosphorylation. Since many protein targets of interest lack structural features that make them amenable to small molecule targeting, development of StIP-TACs may broaden the potential range of protein targets using a PROTAC-mediated proteasomal degradation approach.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1554-8929 1554-8937 1554-8937
DOI:	10.1021/acschembio.4c00237