Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells

Area of Science:

• Molecular Biology
• Drug Discovery
• Proteomics

Background:

• Immunomodulatory imide drugs (IMiDs) like lenalidomide induce protein degradation via zinc finger (ZF) motifs.
• Current IMiDs lack selectivity, degrading unintended ZF-containing proteins (e.g., IKZF1, IKZF3, SALL4).

Purpose of the Study:

• To engineer a selective protein degradation system using modified IMiDs.
• To overcome the lack of specificity in existing ZF-based degron systems.

Main Methods:

• Utilized a "bump-and-hole" strategy to create mutated ZF proteins and novel IMiD analogues.
• Screened 8380 ZF mutants against bumped IMiD analogues for selective binding and degradation.
• Validated the system by inducing degradation of target proteins fused to the engineered degron.

Main Results:

• Developed a bumped IMiD analogue that selectively degrades a mutant ZF degron.
• Demonstrated that the new IMiD analogue does not degrade endogenous ZF proteins (IKZF1, IKZF3, SALL4).
• Successfully applied the system to degrade proteins like CDK9, HPRT1, NanoLuc, and TRIM28.

Conclusions:

• The developed system offers enhanced selectivity for targeted protein degradation.
• This novel approach expands the toolkit for inducible protein degradation in biological research and drug discovery.
• The system holds potential for applications in target validation and therapeutic strategies.