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Fluorescence theranostic PROTACs for real-time visualization of ERα degradation.
- Source :
-
European Journal of Medicinal Chemistry . Mar2024, Vol. 267, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
-
Abstract
- 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 ERα proteins (DC 50 = 0.12 μM) and displaying exceptional anti-proliferative activity against MCF-7 cells (IC 50 = 0.051 μM). 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 real-time, in situ tracking of ERα protein degradation processes, thus may serve as a privileged visual theranostic PROTAC for ERα+ 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. [Display omitted] • Fluorescence imaging blends with therapeutic enable creating novel visual PROTACs. • Fluorescent A3 displays potent ERα degradation and anti-proliferative activities. • Expands PROTAC technology for real-time visualization of ERα protein degradation. [ABSTRACT FROM AUTHOR]
- Subjects :
- *FLUORESCENCE
*DATA visualization
*PROTEOLYSIS
*STOKES shift
*FLUORESCENT probes
Subjects
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 267
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 175569472
- Full Text :
- https://doi.org/10.1016/j.ejmech.2024.116184