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Identification of Functional Protein Regions Through Chimeric Protein Construction

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Published on: January 8, 2019

Rational design of the linkers in targeting chimeras.

Yiping Duan^1,2,3,4, Michelle Y Cai¹, Jinyi Xu⁴

¹Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison Madison WI 53705 USA qhu66@wisc.edu.

Chemical Science

|September 24, 2025

Summary

Targeting chimeras (TACs) offer new ways to degrade proteins, including hard-to-drug targets. Advances in linker design improve TAC efficacy and control, though challenges in optimizing stability and bioavailability remain.

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Area of Science:

Biochemistry
Medicinal Chemistry
Drug Discovery

Background:

Targeting chimeras (TACs) are bifunctional molecules or molecular glues for selective protein degradation.
TACs offer therapeutic potential for diseases intractable to traditional small molecules.
The linker is crucial for TAC spatial conformation and activity.

Purpose of the Study:

To review recent advancements in TAC development.
To summarize linker design strategies for various TACs.
To highlight challenges and future opportunities in TAC linker design.

Main Methods:

Review of recent literature on TACs and linker design.
Categorization of linker strategies (traditional, non-traditional, functionalized).
Analysis of linker impact on TAC efficacy, selectivity, and control.

Main Results:

Innovative linker designs (photo-switchable, cleavable, flexible) enhance TAC performance.
Linker properties significantly influence spatial conformation, activity, and spatiotemporal control.
Challenges persist in balancing linker stability, bioavailability, and pharmacokinetics.

Conclusions:

Optimized linker design is key to advancing TAC therapeutics.
Further research into linker properties can overcome current limitations.
This review provides insights for developing novel TACs in drug discovery.