Discovery of fluorescent theranostic molecular glues for real-time visualization and target degradation toward eEF2K

Abstract

Eukaryotic elongation factor 2 kinase (eEF2K) plays a significant role in tumor cell adaptation under metabolic stress and serves as a promising target for cancer therapy. Nowadays, the research about target protein degradation (TPD) technology is still in the ascendant, which led to the PROTACs and MGs that induce eEF2K degradation. However, few approaches could realize the real-time monitoring of TPD process, hindering the understanding of protein degradation and the effect it caused. In this study, a series of novel fluorescence theranostic probes (TYMJ-01∼06) was rationally designed and synthesized, based on an MG targeting eEF2K. As the representative probe, TYMJ-01 exhibited superior degradation efficiency (DC₅₀ = 82 ± 12.57 nM, Y_min = 27.14 ± 12.6 %) for eEF2K through the ubiquitin–proteasome pathway, as well as outstanding capability of dynamic fluorescence imaging toward intracellular eEF2K degradation in TNBC cells. Furthermore, the probe maintained significant inhibition of cell proliferation, migration, and invasion, and enhanced the antitumor activity of paclitaxel in combination treatment. Therefore, a reliable and efficient toolkit would be provided for eEF2K mechanism study and corresponding drug discovery. Our work could also be beneficial to the study and establishment of TPD and the visualization of a dual-functional system.