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TRIM21-NUP98 Interface Accommodates Structurally Diverse Molecular Glue Degraders.
Yalong Cheng1,2, Longzhi Cao2,3, Panrui Lu2,3
1College of Life Sciences, Beijing Normal University, Beijing 100875, China.
ACS Chemical Biology
|April 9, 2025
Summary
Molecular glue degraders harness E3 ubiquitin ligases for targeted protein destruction. The TRIM21-NUP98 interface can bind diverse molecular glues, enabling new therapeutic strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Molecular glue degraders facilitate targeted protein degradation by linking target proteins with E3 ubiquitin ligases.
- The adaptability of target-E3 interfaces to diverse degraders is not fully understood across all molecular glue targets.
Purpose of the Study:
- To investigate the adaptability of the TRIM21-NUP98 interface to structurally diverse molecular glue degraders.
- To identify novel molecular glue degraders targeting the TRIM21-NUP98 complex.
Main Methods:
- Analysis of public compound toxicity data across numerous cell lines.
- Identification and characterization of novel molecular glue degraders.
- Confirmation of binding at the TRIM21-NUP98 interface for identified compounds.
Main Results:
- Identified PRLX 93936 and BMS-214662 as novel molecular glue degraders engaging the TRIM21-NUP98 interface.
- Confirmed that HGC652, a previously known degrader, also binds to this interface.
- Demonstrated that the TRIM21-NUP98 interface accommodates structurally diverse molecular glue degraders, including (S)-ACE-OH.
Conclusions:
- The TRIM21-NUP98 interface is a versatile binding site for multiple, structurally distinct molecular glue degraders.
- This adaptability suggests potential for developing a broader range of targeted protein degradation therapies.
- Novel degraders like PRLX 93936 and BMS-214662 expand the toolkit for modulating nuclear pore protein levels.
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