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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 ubiquitination machinery. PROTACs comprise a moiety that binds the selected protein, conjugated to a ligand of an E3 ligase. Herein, 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 demonstration with the degradation of two RBPs-a stem cell factor LIN28 and a splicing factor RBFOX1-and showed 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.

Original publication




Journal article


Angew Chem Int Ed Engl

Publication Date





3163 - 3169


Lin28, PROTAC, RNA-binding proteins, oligonucleotides, proteasomal degradation, Base Sequence, Binding Sites, Cell Line, Tumor, Humans, Oligonucleotides, Peptides, Proteolysis, RNA, RNA Splicing Factors, RNA-Binding Proteins, Ubiquitin-Protein Ligases