دورية أكاديمية
أعرض في EDS

Fluorescence theranostic PROTACs for real-time visualization of ERα degradation.

التفاصيل البيبلوغرافية
العنوان: Fluorescence theranostic PROTACs for real-time visualization of ERα degradation.
المؤلفون: Wang X; School of Environmental Ecology and Biological Engineering, Wuhan Institute of Technology, Wuhan, 430205, China; College of Life Sciences, Wuchang University of Technology, Wuhan, Hubei Province, 430223, China., Xin L; State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China., Deng X; State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China., Dong C; State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China., Hu G; School of Environmental Ecology and Biological Engineering, Wuhan Institute of Technology, Wuhan, 430205, China. Electronic address: msnhm123@gmail.com., Zhou HB; State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China. Electronic address: zhouhb@whu.edu.cn.
المصدر: European journal of medicinal chemistry [Eur J Med Chem] 2024 Mar 05; Vol. 267, pp. 116184. Date of Electronic Publication: 2024 Feb 01.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
مواضيع طبية MeSH: Proteolysis Targeting Chimera* , Estrogen Receptor alpha*/metabolism, Humans ; Proteolysis ; Precision Medicine ; Ubiquitin-Protein Ligases/metabolism ; Proteins/metabolism
مستخلص: 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.
Competing Interests: Declaration of competing interest The authors declare no competing financial interest.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
المشرفين على المادة: 0 (Proteolysis Targeting Chimera)
0 (Estrogen Receptor alpha)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
0 (Proteins)
تواريخ الأحداث: Date Created: 20240206 Date Completed: 20240226 Latest Revision: 20240226
رمز التحديث: 20240226
DOI: 10.1016/j.ejmech.2024.116184
PMID: 38320426
قاعدة البيانات: MEDLINE
الوصف
تدمد:1768-3254
DOI:10.1016/j.ejmech.2024.116184