Design of a dual ERK5 kinase activation and autophosphorylation inhibitor to block cancer stem cell activity

[Display omitted] The importance of ERK5 kinase signaling in tumorigenicity, metastasis, and drug resistance of cancer stem cells (CSCs) has been recognized recently, and we report a unique dual inhibitor that blocks binding of the ERK5 activator and ERK5 autophosphorylation simultaneously. The conventional ATP-binding site inhibitors have not yet yielded expected level of anti-cancer effects, due to complexities in converting ERK5 activation into CSC biological effects. We designed the first ERK5-targeted anti-CSC dual active hetero-bivalent inhibitor that blocks the regulatory peptide interaction involved in ERK5 kinase activation and that simultaneously inhibits the conventional ATP-binding pocket as well. We utilized two assay systems to independently prove disruption of these two ERK5 activities via a single compound. We also showed that this compound inhibited CSC activities, such as colony formation, cell proliferation, and migration.