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- W4313379823 abstract "Abstract Engineered destruction of target proteins by recruitment to the cell’s degradation machinery has emerged as a promising strategy in drug discovery. The majority of molecules that facilitate targeted degradation do so via a select number of ubiquitin ligases, restricting this therapeutic approach to tissue types that express the requisite ligase. Here, we describe a new strategy of targeted protein degradation through direct substrate recruitment to the 26S proteasome. The proteolytic complex is essential and abundantly expressed in all cells; however, proteasomal ligands remain scarce. We identify potent peptidic macrocycles that bind directly to the 26S proteasome subunit PSMD2, with a 2.5-Å-resolution cryo-electron microscopy complex structure revealing a binding site near the 26S pore. Conjugation of this macrocycle to a potent BRD4 ligand enabled generation of chimeric molecules that effectively degrade BRD4 in cells, thus demonstrating that degradation via direct proteasomal recruitment is a viable strategy for targeted protein degradation." @default.
- W4313379823 created "2023-01-06" @default.
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- W4313379823 date "2022-12-28" @default.
- W4313379823 modified "2023-10-17" @default.
- W4313379823 title "Targeted degradation via direct 26S proteasome recruitment" @default.
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- W4313379823 doi "https://doi.org/10.1038/s41589-022-01218-w" @default.
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