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

Recent interest in the role that extracellular signal-regulated kinase 5 (ERK5) plays in various diseases, partic-ularly 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.

Automated summary

Recent interest has grown in the role of ERK5 in diseases like cancer and inflammation. However, current ERK5 inhibitors cannot replicate the effects of genetic loss of ERK5, suggesting its non-kinase roles. To explore this, researchers developed a potent and selective ERK5 degrader, INY-06-061. However, unlike genetic knockdown, its degradation of ERK5 did not have the expected effects in cancer cells or endothelial cells.