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- W4313608370 abstract "While proteolysis-targeting chimeras (PROTACs) are showing promise for targeting previously undruggable molecules, their application has been limited by difficulties in identifying suitable ligands and undesired on-target toxicity. Aptamers can virtually recognize any protein through their unique and switchable conformations. Here, by exploiting aptamers as targeting warheads, we developed a novel strategy for inducible degradation of undruggable proteins. As a proof of concept, we chose oncogenic nucleolin (NCL) as the target and generated a series of NCL degraders, and demonstrated that dNCL#T1 induced NCL degradation in a ubiquitin-proteasome-dependent manner, thereby inhibiting NCL-mediated breast cancer cell proliferation. To reduce on-target toxicity, we further developed a light-controllable PROTAC, opto-dNCL#T1, by introducing a photolabile complementary oligonucleotide to hybridize with dNCL#T1. UVA irradiation liberated dNCL#T1 from caged opto-dNCL#T1, leading to dNCL#T1 activation and NCL degradation. These results indicate that aptamer-based PROTACs are a viable alternative approach to degrade proteins of interest in a highly tunable manner." @default.
- W4313608370 created "2023-01-07" @default.
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- W4313608370 date "2023-01-06" @default.
- W4313608370 modified "2023-10-14" @default.
- W4313608370 title "Inducible Degradation of Oncogenic Nucleolin Using an Aptamer-Based PROTAC" @default.
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- W4313608370 doi "https://doi.org/10.1021/acs.jmedchem.2c01557" @default.
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