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Synfacts 2025; 21(07): 744
DOI: 10.1055/a-2601-4541
Innovative Drug Discovery and Development

Evading E3 Ligase Necessity in PROTACs via the ByeTAC

Contributor(s):
Dirk H. Trauner
,
Zoe Sessions
Loy CA, Ali EMH, Seabrook LJ, Harris Jr TJ, Kragness KA, Albrecht L, Trader DJ *. University of California, Irvine, USA
ByeTAC: Bypassing E-Ligase-Targeting Chimeras for Direct Proteasome Degradation.

J. Med. Chem. 2025;
68: 9694-9705
DOI: 10.1021/acs.jmedchem.5c00485
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Keywords

proteasomal degradation - PROTAC - E3 ligases

Significance

PROTACs have revolutionized targeted protein degradation by recruiting E3 ligases to ubiquitinate proteins of interest (POIs), marking them for proteasomal degradation. This work overcomes PROTAC reliance on E3 ligases by directly recruiting POIs to the 26S proteasome, enabling ubiquitin-independent degradation.


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Comment

The authors introduce ByeTACs, bifunctional molecules that link a POI-binding ligand to a small-molecule recruiter of the Rpn-13 subunit of the proteasome. This design enables direct proteasomal degradation without ubiquitination. They demonstrate effective degradation of both engineered Halo-tag constructs and endogenous targets, including BRD4 and BTK. Bypassing the E3 ligase requirement, this approach significantly broadens the scope of degradable targets and diversifies protein-targeting strategies.


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Publication History

Article published online:
23 June 2025

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