Related Experiment Video
Updated: Jan 10, 2026
15:13
Structure-function Studies in Mouse Embryonic Stem Cells Using Recombinase-mediated Cassette Exchange
Published on: April 27, 2017
11.5K
Design of Tissue-Selective PROTACs Through Recruiting E3 Ligase Scaffolding Protein MAGEA11
Isabella E Jacobsen1, Rui Shi2, Cole R Scholtz1
1Department of Chemistry, College of Science and Engineering, University of Minnesota, 207 Pleasant St SE, Minneapolis, MN 55455, USA.
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
This study introduces the first Proteolysis Targeting Chimera (PROTAC) that uses the tissue-specific E3 ligase MAGEA11 to degrade Bromodomain and Extra-Terminal domain (BET) proteins. This approach offers enhanced specificity for cancer-restricted protein degradation.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis targeting chimeras (PROTACs) are an emerging therapeutic strategy that hijacks the ubiquitin-proteasome system to induce protein degradation.
- Current PROTACs primarily utilize ubiquitously expressed E3 ligases, limiting their specificity.
- Tissue-specific E3 ligases offer a promising avenue for developing more targeted protein degraders.
Purpose of the Study:
- To develop the first PROTAC that recruits the tissue-specific E3 ligase scaffolding protein MAGEA11.
- To synthesize and screen a library of MAGEA11-recruiting PROTACs targeting Bromodomain and Extra-Terminal domain (BET) proteins.
- To evaluate the specificity and efficacy of MAGEA11-recruiting PROTACs in cancer cell lines.
Main Methods:
- Synthesis of a library of BET-targeting PROTACs designed to recruit MAGEA11.
- Screening of PROTAC library in osteosarcoma U2OS cells to identify lead compounds.
- Characterization of lead compound 105B's degradation activity, specificity, and mechanism of action in various cell lines.
Main Results:
- Identification of lead compound 105B, a potent MAGEA11-recruiting PROTAC against BET proteins.
- Compound 105B demonstrated potent and selective degradation of BET proteins in osteosarcoma and esophageal squamous cell carcinoma cell lines.
- Degradation was specific to MAGEA11-expressing cells, with no observed effect in MAGEA11-deficient HEK293T cells.
- Mechanistic studies confirmed dependence on the ubiquitin-proteasome system and engagement of MAGEA11 and BRD4.
- 105B reduced levels of key BET-regulated genes (c-Myc, RUNX2, KRT14), but further optimization is needed for selective cytotoxicity.
Conclusions:
- This work reports the first PROTAC utilizing the tissue-specific E3 ligase MAGEA11 for cancer-restricted degradation of BET proteins.
- MAGEA11-recruiting PROTACs represent a promising strategy for developing targeted cancer therapies with reduced off-target effects.
- Further development of MAGEA11-recruiting degraders is warranted to enhance selective cytotoxicity and therapeutic potential.
