Targeted Degradation of Protein Kinase A via a Stapled Peptide PROTAC

ACS Chem Biol. 2024 Sep 20;19(9):1888-1895. doi: 10.1021/acschembio.4c00237. Epub 2024 Aug 13.

Abstract

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.

MeSH terms

  • Cyclic AMP-Dependent Protein Kinases* / metabolism
  • Humans
  • Peptides* / chemistry
  • Peptides* / metabolism
  • Peptides* / pharmacology
  • Phosphorylation / drug effects
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis* / drug effects
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Cyclic AMP-Dependent Protein Kinases
  • Peptides
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex