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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.
Abstract:
Proteolysis targeting chimeras (PROTACs) are an emerging therapeutic modality that induces protein degradation by recruiting E3 ligases. Most reported PROTACs recruit ubiquitously expressed E3 ligases, such as cereblon and the von Hippel-Lindau tumor suppressor. Of the additional 600+ E3 ligases, recruiting those with tissue-restricted expression is attractive for increasing the specificity of PROTACs. To this end, tissue-specific E3 ligases or E3 ligase-associated proteins that can be recruited for targeted protein degradation need to be identified. This work describes the first reported PROTAC that recruits the tissue-specific E3 ligase scaffolding protein MAGEA11. As an initial demonstration, a library of bromodomain and extra-terminal domain (BET)-targeting PROTACs that recruit MAGEA11 was synthesized. The library was screened in osteosarcoma U2OS cells, identifying lead compound 105B. 105B potently degrades BET proteins in U2OS osteosarcoma cell lines (BRD4 DC50 = 0.130 nM, Dmax = 78%) and KYSE180 esophageal squamous cell carcinoma cell lines (DC50 = 40 nM, Dmax = 70%), but shows no degradation in non-cancerous, MAGEA11-deficient HEK293T cells. Mechanistic studies confirmed 105B's dependence on the ubiquitin-proteasome system and engagement of both MAGEA11 and BRD4. 105B decreased levels of BET-regulated gene products c-Myc, RUNX2, and KRT14; however, improvements are still necessary to affect selective cytotoxicity. This work reports the first example of a PROTAC recruiting a tissue-specific E3 ligase for cancer-restricted degradation of BET proteins and highlights the need for further development of MAGEA11-recruiting degraders.
Insights
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.
