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Insights into the Design of MYC-Targeting Proteolysis Targeting Chimeras (PROTACs)
Abdallah M Alfayomy1,2, Sven Hagemann3, Matthias Schmidt1
1Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany.
Abstract:
The oncogenic transcription factor MYC is a key driver of the development and progression of various types of cancer, but its intrinsically disordered structure and dependence on protein-protein interactions make it a difficult therapeutic target. Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that can induce the selective degradation of disease-relevant proteins. In this study, we report the synthesis and biological testing of a series of novel MYC-targeted PROTACs derived from the MYC inhibitor EN4. These ligands were conjugated to cereblon (CRBN) or von Hippel-Lindau (VHL) E3 ligase recruiters using different linker architectures and connection sites. The resulting PROTACs were synthesized in high purity and characterized analytically. Cellular evaluation in HEK293T, Panc-1 and HCT-116 cancer cells revealed only moderate reductions in cell viability. Unfortunately, none of the synthesized PROTACs showed detectable MYC degradation at biologically relevant concentrations. Testing the stability of the PROTACs in microsomes showed rapid degradation, which may be a reason for the observed inactivity in cells. These results underscore the significant challenges associated with the targeted protein degradation of intrinsically disordered transcription factors such as MYC. Further studies are necessary to identify additional causes for the lack of MYC degradation and to optimize the chemical structures accordingly.
Insights
Researchers developed novel Proteolysis-Targeting Chimeras (PROTACs) to degrade the MYC oncoprotein, a challenging cancer target. However, these PROTACs showed limited efficacy due to rapid degradation, highlighting difficulties in targeting intrinsically disordered proteins.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- The MYC oncogenic transcription factor drives cancer progression but is difficult to target therapeutically due to its disordered structure.
- Proteolysis-targeting chimeras (PROTACs) offer a novel approach for selective protein degradation.
Purpose of the Study:
- To synthesize and evaluate novel MYC-targeted PROTACs derived from the EN4 inhibitor.
- To assess the efficacy of these PROTACs in degrading MYC and reducing cancer cell viability.
Main Methods:
- Synthesis of PROTACs conjugating EN4 to cereblon (CRBN) or von Hippel-Lindau (VHL) E3 ligase recruiters.
- Analytical characterization and cellular evaluation in HEK293T, Panc-1, and HCT-116 cancer cells.
- Assessment of PROTAC stability in microsomes.
Main Results:
- Novel MYC-targeted PROTACs were synthesized with high purity.
- Cellular assays showed only moderate reductions in cancer cell viability.
- No detectable MYC degradation was observed at relevant concentrations, potentially due to rapid PROTAC degradation in microsomes.
Conclusions:
- Targeted protein degradation of intrinsically disordered transcription factors like MYC presents significant challenges.
- Further optimization of PROTAC chemical structures and investigation into degradation mechanisms are required for MYC-targeted therapies.
