Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands

Area of Science:

• Molecular Biology
• Cancer Research
• Chemical Biology

Background:

• The TRIM24 protein, a transcriptional regulator, is implicated in various cancers.
• Selective inhibitors targeting TRIM24's bromodomain show limited anti-cancer effects.
• The functional relevance of protein pockets in disease often differs from their druggability.

Purpose of the Study:

• To investigate TRIM24 as a cancer dependency.
• To develop novel therapeutic strategies beyond direct bromodomain inhibition.
• To explore TRIM24 degradation as a means to control cancer cell proliferation.

Main Methods:

• Development of heterobifunctional degraders targeting TRIM24 (dTRIM24).
• Utilizing the VHL E3 ubiquitin ligase for TRIM24 degradation.
• Genome-wide analysis of TRIM24 loss effects on chromatin and gene expression.
• Comparative studies of TRIM24 degradation versus bromodomain inhibition.

Main Results:

• dTRIM24 induces potent and selective degradation of TRIM24.
• TRIM24 loss significantly impacts genome-wide chromatin localization and gene control.
• TRIM24 is identified as a critical dependency in acute leukemia.
• TRIM24 degradation demonstrates superior anti-proliferative activity compared to bromodomain inhibition.

Conclusions:

• TRIM24 degradation is a promising therapeutic strategy for cancers, including acute leukemia.
• Heterobifunctional degraders can overcome limitations of traditional inhibitors for certain protein targets.
• dTRIM24 serves as a valuable chemical probe for studying TRIM24 function and its role in cancer.