State-selective small molecule degraders that preferentially remove aggregates and oligomers

Jakub Luptak, Dean Clift, Aamir Mukadam, Jonathan Benn, Tyler Rhinesmith, Stephen H. McLaughlin, Amy C. Dodds, Jerson E. Lapetaje, Matylda Sczaniecka-Clift, David J. France, William A. McEwan and Leo C. James ()
Additional contact information
Jakub Luptak: Francis Crick Avenue, MRC Laboratory of Molecular Biology
Dean Clift: Francis Crick Avenue, MRC Laboratory of Molecular Biology
Aamir Mukadam: Hills Road, UK Dementia Research Institute at the University of Cambridge, Department of Clinical Neurosciences
Jonathan Benn: Hills Road, UK Dementia Research Institute at the University of Cambridge, Department of Clinical Neurosciences
Tyler Rhinesmith: Francis Crick Avenue, MRC Laboratory of Molecular Biology
Stephen H. McLaughlin: Francis Crick Avenue, MRC Laboratory of Molecular Biology
Amy C. Dodds: University of Glasgow, School of Chemistry, Joseph Black Building
Jerson E. Lapetaje: University of Glasgow, School of Chemistry, Joseph Black Building
Matylda Sczaniecka-Clift: Francis Crick Avenue, MRC Laboratory of Molecular Biology
David J. France: University of Glasgow, School of Chemistry, Joseph Black Building
William A. McEwan: Hills Road, UK Dementia Research Institute at the University of Cambridge, Department of Clinical Neurosciences
Leo C. James: Francis Crick Avenue, MRC Laboratory of Molecular Biology

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract TRIM21 is a unique E3 ligase that uses a clustering-based activation mechanism to degrade complex multimeric substrates. This activity underpins the targeted protein degradation technology Trim-Away and genetically encoded degraders that selectively target aggregated tau protein and prevent tauopathy. Here we describe small molecules that mimic TRIM21’s natural epitope and function as either effective inhibitors or potent and selective degraders called TRIMTACs. TRIMTACs mediate degradation as rapidly as PROTACs but can also selectively degrade specific protein pools depending on assembly state. We demonstrate the utility of this state-specific degradation by selectively removing the pro-inflammatory signalling protein Myd88 when assembled into the Myddosome and the cell-death protein RIPK3 when polymerised into the Necrosome. We further show that TRIMTACs can inhibit seeded tau aggregation under conditions where a PROTAC is ineffective. These results highlight that TRIM21’s clustering-based activation can be exploited by small molecule degraders to carry out state-selective degradation of therapeutic targets.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65454-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65454-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65454-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().