2. Academic Validation
  3. Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation

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

  • Cell Chem Biol. 2022 Oct 6;S2451-9456(22)00352-X. doi: 10.1016/j.chembiol.2022.09.004.
Inchul You 1,  Katherine A Donovan 2,  Noah M Krupnick 3,  Andrew S Boghossian 4,  Matthew G Rees 4,  Melissa M Ronan 4,  Jennifer A Roth 4,  Eric S Fischer 2,  Eric S Wang 5,  Nathanael S Gray 6
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 5 Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. Electronic address: [email protected].
  • 6 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 36220104 DOI: 10.1016/j.chembiol.2022.09.004
Abstract

Recent interest in the role that extracellular signal-regulated kinase 5 (ERK5) plays in various diseases, particularly Cancer and inflammation, has grown. Phenotypes observed from genetic knockdown or deletion of ERK5 suggested that targeting ERK5 could have therapeutic potential in various disease settings, motivating the development ATP-competitive ERK5 inhibitors. However, these inhibitors were unable to recapitulate the effects of genetic loss of ERK5, suggesting that ERK5 may have key kinase-independent roles. To investigate potential non-catalytic functions of ERK5, we report the development of INY-06-061, a potent and selective heterobifunctional degrader of ERK5. In contrast to results reported through genetic knockdown of ERK5, INY-06-061-induced ERK5 degradation did not induce anti-proliferative effects in multiple Cancer cell lines or suppress inflammatory responses in primary endothelial cells. Thus, we developed and characterized a chemical tool useful for validating phenotypes reported to be associated with genetic ERK5 ablation and for guiding future ERK5-directed drug discovery efforts.

Keywords

ERK5; PROTAC; targeted protein degradation.

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