Fluorescence theranostic PROTACs for real-time visualization of ER degradation

Proteolysis targeting chimera (PROTAC) technology, a groundbreaking strategy for degradation of pathogenic proteins by hijacking of the ubiquitin-proteasome-system has become a promising strategy in drug design. However, the real -time monitoring and visualization of protein degradation processes have been long-standing challenges in the realm of drug development. In this research, we sought to amalgamate the highly efficient protein-degrading capabilities of PROTAC technology with the visualization attributes of fluorescent probes, with the potential to pave the path for the design and development of a novel class of visual PROTACs. These novel PROTACs uniquely possess both fluorescence imaging and therapeutic characteristics, all with the goal of enabling real -time observations of protein degradation processes. Our approach involved the utilization of a high ER-targeting fluorescent probe, previously reported in our laboratory, which served as a warhead that specifically binds to the protein of interest (POI). Additionally, a VHL ligand for recruiting E3 ligase and linkers of various lengths were incorporated to synthesize a series of novel ER-inherent fluorescence PROTACs. Among them, compound A3 demonstrated remarkable efficiency in degrading ER alpha proteins (DC50 = 0.12 mu M) and displaying exceptional anti-proliferative activity against MCF-7 cells (IC50 = 0.051 mu M). Furthermore, it exhibited impressive fluorescence imaging performance, boasting an emission wavelength of up to 582 nm, a Stokes shift of 116 nm, and consistent optical properties. These attributes make it especially suitable for the realtime, in situ tracking of ER alpha protein degradation processes, thus may serve as a privileged visual theranostic PROTAC for ER alpha+ breast cancer. This study not only broadens the application spectrum of PROTAC technology but also introduces a novel approach for real -time visualization of protein degradation processes, ultimately enhancing the diagnostic and treatment efficacy of PROTACs.