Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation. Issue 11 (17th November 2022)

• Record Type: Journal Article
• Authors: You, Inchul; Donovan, Katherine A.; Krupnick, Noah M.; Boghossian, Andrew S.; Rees, Matthew G.; Ronan, Melissa M.; Roth, Jennifer A.; Fischer, Eric S.; Wang, Eric S.; Gray, Nathanael S.
• Is Part Of: Cell chemical biology. Volume 29:Issue 11(2022)
• Page Start: 1630
• Page End: 1638.e7
• Publication Date: 2022-11-17
• Subjects: ERK5 -- PROTAC -- targeted protein degradation; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2022.09.004
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical abstract: Highlights: PROTACs that incorporate XMD17-109 and JWG-071 are not selective for ERK5 INY-06-061 is a potent and highly selective heterobifunctional degrader of ERK5 INY-06-061 treatment does not compromise viability in multiple cancer cell lines INY-06-061 does not affect pro-inflammatory cytokine secretion in endothelial cells Abstract : You et al. report the development and characterization of INY-06-061, a potent and highly selective ERK5 degrader. While pharmacological ERK5 degradation did not result in potent anti-proliferative or anti-inflammatory effects in this study, INY-06-061 can serve as a useful chemical probe to further dissect/investigate the biological functions of ERK5.