Immunomodulatory imide drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, can be used to induce degradation of a protein of interest that is fused to a short zinc finger (ZF) degron motif. These IMiDs, however, also induce degradation of endogenous neosubstrates, including IKZF1 and IKZF3. To improve degradation selectivity, we took a bump-and-hole approach to design and screen bumped IMiD analogs against 8380 ZF mutants. This yielded a bumped IMiD analog that induces efficient degradation of a mutant ZF degron, while not affecting other cellular proteins, including IKZF1 and IKZF3. In proof-of-concept studies, this system was applied to induce efficient degradation of TRIM28, a disease-relevant protein with no known small molecule binders. We anticipate that this system will make a valuable addition to the current arsenal of degron systems for use in target validation.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10979945PMC
http://dx.doi.org/10.1101/2024.03.15.585309DOI Listing

Publication Analysis

Top Keywords

induce degradation
8
including ikzf1
8
ikzf1 ikzf3
8
bumped imid
8
efficient degradation
8
degradation
6
orthogonal imid-degron
4
imid-degron pairs
4
induce
4
pairs induce
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!