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Modular Assembled Targeting Chimera Enables Multimodal Targeted Protein Degradation
Wentao Zhu1, Wenqian Zhang1, Yinmiao Wang1
1School of Chemistry, Sun Yat-sen University, Guangzhou 510006, China.
JACS Au
|November 28, 2025
Summary
A new multimodal modular assembled targeting chimera (multi-MOATAC) strategy enables in situ assembly of potent degraders. This approach enhances targeted protein degradation efficiency and shows promise for developing novel therapeutics.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Targeted protein degradation (TPD) offers advantages over traditional protein inhibition.
- Challenges remain in developing potent degraders with optimal drug-like properties.
Purpose of the Study:
- To develop a novel strategy for in situ assembly of targeted protein degraders.
- To enhance degradation efficiency and broaden the applicability of TPD therapeutics.
Main Methods:
- Developed a multimodal modular assembled targeting chimera (multi-MOATAC) strategy.
- Utilized intracellular click chemistry for in situ assembly of ligand modules.
- Evaluated degradation efficiency for BRD4, EGFR, and ALK targets.
Main Results:
- Achieved significantly enhanced degradation efficiency with trivalent self-assembling degraders (DC50 of 4.6 ± 1.3 nM for BRD4).
- Demonstrated broad applicability across nuclear, membrane, and cytoplasmic targets.
- Confirmed superior antitumor efficacy of trivalent self-assembling PROTACs in vivo.
Conclusions:
- The multi-MOATAC strategy provides a modular and scalable approach for developing novel degraders.
- This strategy holds potential for advancing tissue-specific therapeutics and treating related diseases.
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