Development of a chaperone-mediated protein degrader targeting ERK5 that efficaciously reduces tumor growth

The heat shock protein 90 (HSP90) chaperone complex directs either the proper folding or proteasome-mediated degradation of its substrate proteins. Extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase family, has been implicated in the biology of several cancer types. To harness the protein-degradation activity of this HSP90 chaperone complex, we developed a novel targeted protein degradation technology, termed Chaperone-Mediated Protein Degradation (CHAMP), and an ERK5-CHAMP was designed to induce chemical proximity between HSP90 and ERK5 to induce ERK5 degradation. In this study, potential degraders targeting ERK5, termed ERK5-CHAMPs, were developed. An ERK5-CHAMP was identified to degrade ERK5 protein via ubiquitin-proteasome system (UPS) by western blot in vitro and in vivo, and to reduce tumor growth in vitro by cell viability assay, FACS and in vivo by mouse xenograft models. The pharmacokinetic (PK) properties of ERK5-CHAMP were also tested through LC-MS. Moreover, immunofluorescence and a reporter system were used to explore the mechanism associated with ERK5-CHAMP. The treatment of cancer cells with ERK5-CHAMP resulted in proteasome-dependent ERK5 degradation and prevented ERK5 nuclear accumulation. ERK5-CHAMP treatment led to cell cycle arrest, increased apoptosis, and reduced cell viability. in vivo, ERK5-CHAMP significantly reduced tumor growth in mouse xenograft tumor models and preferentially accumulated in tumors relative to levels in normal tissues. These data highlight the potential of CHAMP degraders targeting ERK5 for cancer treatment. CHAMP is a novel, small-molecule targeted protein degradation technology. ERK5-CHAMP resulted in proteasome-dependent ERK5 degradation and hampered ERK5 nuclear accumulation, displayed tumor-selective pharmacokinetic properties and significantly reduced tumor growth. This suggests that ERK5-targeting CHAMPs represent a promising new approach to disrupt the entire function of ERK5 and could be exploited for cancer treatment.