RNA-PROTACs - degraders of RNA-binding proteins.

Ghidini A; Cléry A; Halloy F; Allain FHT; Hall J

doi:10.1002/anie.202012330

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Journal article

RNA-PROTACs - degraders of RNA-binding proteins.

Ghidini A ETH Zurich: Eidgenossische Technische Hochschule Zurich, Institut for Pharmaceutical Sceinces, SWITZERLAND.
Cléry A ETH Zurich: Eidgenossische Technische Hochschule Zurich, Institute for Biochemistry, SWITZERLAND.
Halloy F ETH Zürich: Eidgenossische Technische Hochschule Zurich, Institute of Pharmaceutical Sciences, SWITZERLAND.
Allain FHT ETH Zurich: Eidgenossische Technische Hochschule Zurich, Institute for Biochemistry, SWITZERLAND.
Hall J ETH Zurich, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosci, Vladimir-Prelog-Weg 4, 8093, Zürich, SWITZERLAND.

2020-10-27

Published in:

Angewandte Chemie (International ed. in English). - 2020

English Defects in the functions of RNA binding proteins (RBPs) are at the origin of many diseases, however targeting RBPs with conventional drugs has proven difficult. PROTACs are a new class of drugs that mediate selective degradation of a target protein through a cell's ubiquitylation machinery. PROTACs comprise a moiety that binds the selected protein, conjugated to a ligand of an E3 ligase. Here, we introduce RNA-PROTACs as a new concept in the targeting of RBPs. These chimeric structures employ small RNA mimics as targeting groups that dock the RNA-binding site of the RBP, whereupon a conjugated E3-recruiting peptide derived from the HIF-1α protein directs the RBP for proteasomal degradation. We performed a proof-of-concept with the degradation of two RBPs - a stem cell factor LIN28 and a splicing factor RBFOX1 - and demonstrated their use in cancer cell lines. The RNA-PROTAC approach opens the way to rapid, selective targeting of RBPs in a rational and general fashion.

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