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Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation

Inchul You1, Katherine A Donovan2, Noah M Krupnick3

  • 1Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA.

Cell Chemical Biology
|October 11, 2022
PubMed

Insights

Researchers developed a new tool to study extracellular signal-regulated kinase 5 (ERK5) independent of its kinase activity. This chemical probe helps validate ERK5

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Extracellular signal-regulated kinase 5 (ERK5) is implicated in cancer and inflammation.
  • Genetic studies suggest therapeutic potential for targeting ERK5.
  • Existing ATP-competitive inhibitors do not fully replicate genetic ERK5 loss phenotypes.

Purpose of the Study:

  • To investigate potential kinase-independent roles of ERK5.
  • To develop a chemical tool for studying ERK5's non-catalytic functions.
  • To create a probe that can validate phenotypes associated with genetic ERK5 ablation.

Main Methods:

  • Development of INY-06-061, a heterobifunctional degrader of ERK5.
  • Testing INY-06-061 in cancer cell lines for anti-proliferative effects.
  • Assessing INY-06-061's impact on inflammatory responses in primary endothelial cells.

Main Results:

  • INY-06-061 selectively degrades ERK5.
  • ERK5 degradation by INY-06-061 did not inhibit proliferation in cancer cell lines.
  • Degradation of ERK5 did not suppress inflammatory responses in endothelial cells.

Conclusions:

  • ERK5 may have critical kinase-independent functions.
  • The developed chemical tool, INY-06-061, is valuable for studying ERK5.
  • This tool aids in validating genetic phenotypes and guiding future drug discovery for ERK5.
Keywords:
ERK5PROTACtargeted protein degradation

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