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

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• TRIM21 is an E3 ligase utilizing a clustering mechanism for substrate degradation.
• This mechanism is the basis for Trim-Away technology and genetically encoded degraders targeting tau protein and preventing tauopathy.

Purpose of the Study:

• To develop small molecules (TRIMTACs) mimicking TRIM21's epitope for targeted protein degradation.
• To investigate the state-selective degradation capabilities of TRIMTACs.
• To assess TRIMTACs' efficacy in inhibiting tau aggregation.

Main Methods:

• Design and synthesis of small molecules (TRIMTACs) that mimic TRIM21's epitope.
• Evaluation of TRIMTACs' degradation kinetics compared to PROTACs.
• Demonstration of state-specific degradation of Myd88 and RIPK3.
• Assessment of TRIMTACs' ability to inhibit seeded tau aggregation.

Main Results:

• TRIMTACs function as potent and selective inhibitors or degraders.
• TRIMTACs achieve degradation as rapidly as PROTACs.
• TRIMTACs enable state-specific degradation, targeting assembled Myd88 (Myddosome) and polymerized RIPK3 (Necrosome).
• TRIMTACs effectively inhibit seeded tau aggregation, outperforming PROTACs in certain conditions.

Conclusions:

• TRIM21's clustering-based activation can be leveraged by small molecule degraders (TRIMTACs).
• TRIMTACs offer a novel approach for state-selective degradation of therapeutic targets.
• TRIMTACs show promise in treating diseases like tauopathy.