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Tytuł pozycji:

Azo-PROTAC: Novel Light-Controlled Small-Molecule Tool for Protein Knockdown.

Tytuł:
Azo-PROTAC: Novel Light-Controlled Small-Molecule Tool for Protein Knockdown.
Autorzy:
Jin YH; State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Lu MC; State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Wang Y; State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Shan WX; State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Wang XY; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
You QD; State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Jiang ZY; State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Źródło:
Journal of medicinal chemistry [J Med Chem] 2020 May 14; Vol. 63 (9), pp. 4644-4654. Date of Electronic Publication: 2020 Mar 19.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
MeSH Terms:
Azo Compounds/*pharmacology
Dasatinib/*analogs & derivatives
Dasatinib/*pharmacology
Lenalidomide/*analogs & derivatives
Lenalidomide/*pharmacology
Adaptor Proteins, Signal Transducing/metabolism ; Azo Compounds/chemical synthesis ; Azo Compounds/radiation effects ; Cell Line, Tumor ; Dasatinib/radiation effects ; Fusion Proteins, bcr-abl/metabolism ; Humans ; Lenalidomide/radiation effects ; Ligands ; Proteolysis/drug effects ; Stereoisomerism ; Ubiquitin-Protein Ligases ; Ubiquitination/drug effects ; Ultraviolet Rays
Substance Nomenclature:
0 (Adaptor Proteins, Signal Transducing)
0 (Azo Compounds)
0 (CRBN protein, human)
0 (Ligands)
0 (abl-bcr fusion protein, human)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
EC 2.7.10.2 (Fusion Proteins, bcr-abl)
F0P408N6V4 (Lenalidomide)
RBZ1571X5H (Dasatinib)
Entry Date(s):
Date Created: 20200311 Date Completed: 20201102 Latest Revision: 20201210
Update Code:
20240105
DOI:
10.1021/acs.jmedchem.9b02058
PMID:
32153174
Czasopismo naukowe
Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells. The light-induced configuration change can switch the active state to induce protein degradation activity, which can be reversely controlled by light exposure in intact cells. We compared the protein degradation abilities of Azo-PROTACs with different configurations and linker lengths. Using the stable form with the best degradation ability against the BCR-ABL fusion and ABL proteins in myelogenous leukemia K562 cells, we showed that Azo-PROTAC combines the potent protein knockdown and facile cell uptake properties of the small-molecule PROTAC with a reversible photoswitchability, offering a promising chemical knockdown strategy based on the light-induced reversible on/off properties.

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