Related Experiment Video
Updated: Aug 5, 2026
10:44
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Two Mechanisms One Molecule: Developing a 'Truly' Bifunctional Degrader Targeting Rpn13 and CRBN
Cody A Loy1,2, Shawn E Vinogradsky1,2, Darci J Trader1,2,3
1Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, California92617, United States.
Journal of the American Chemical Society
|July 30, 2026
Summary
Researchers developed "Truly" degraders, novel bifunctional molecules for targeted protein degradation. These molecules simultaneously engage ubiquitin-dependent and -independent pathways, offering a new strategy for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Targeted protein degradation (TPD) is a key therapeutic strategy, but current methods primarily rely on ubiquitin ligases.
- Previous work introduced ByeTACs for E-ligase independent degradation.
- Existing TPD approaches have limitations in targeting specific proteins.
Purpose of the Study:
- To develop a new class of bifunctional molecules, "Truly" degraders, that utilize dual degradation mechanisms.
- To investigate the efficacy of "Truly" degraders in degrading disease-relevant proteins.
- To explore the potential of "Truly" degraders in cancer therapy.
Main Methods:
- Design and synthesis of "Truly" degraders, combining ligands for Rpn13 and cereblon (CRBN).
- Structure-guided optimization of linker length for efficient substrate processing.
- Evaluation of degradation efficacy and cytotoxicity in various cancer cell lines.
Main Results:
- The PEG4 derivative (Truly-4) effectively depleted Rpn13 and CRBN in cancer cells.
- Truly-4 achieved noncovalent degradation of full-length Rpn13, a novel approach.
- Degradation of Rpn13 occurred via CRBN-dependent E3 ligase activity, while CRBN degraded independently.
- Truly-4 exhibited selective cytotoxicity in cancer cells but not healthy cells.
Conclusions:
- "Truly" degraders represent a new class of bifunctional molecules for targeted protein degradation.
- Dual-mechanism degradation offers a strategy to uncouple target engagement from toxicity.
- Proteasome receptors are viable targets for selective destruction of disease-related proteins.
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