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Applications and Limitations of Oxime-Linked "Split PROTACs".
1Department of Chemistry, UF Scripps Biomedical Research, 120 Scripps Way, Jupiter, FL 33458, USA.
Chembiochem : a European Journal of Chemical Biology
|July 8, 2022
Summary
Split proteolysis targeting chimeras (PROTACs) enable combinatorial screening of E3 Ubiquitin Ligase and target protein ligands. Oxime chemistry facilitates PROTAC assembly, but in situ coupling is inefficient at low concentrations.
Area of Science:
- Chemical Biology
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis targeting chimeras (PROTACs) are promising drug leads and probes.
- PROTAC efficacy depends on linker optimization between E3 Ubiquitin Ligase (E3 Ubl) and target protein (TP) ligands.
- Current optimization methods are labor-intensive.
Purpose of the Study:
- To develop a "split PROTAC" strategy for combinatorial screening of PROTAC components.
- To utilize oxime chemistry for efficient PROTAC assembly.
- To assess the efficiency of in situ PROTAC formation.
Main Methods:
- Designing E3 Ubl and TP ligands with residues for oxime coupling.
- Mixing PROTAC components at high concentrations before cell addition.
- Evaluating PROTAC assembly and activity in cellular contexts.
Main Results:
- PROTAC assembly via oxime ligation is efficient when components are pre-mixed at high concentrations.
- In situ coupling of E3 Ubl and TP ligands is inefficient at lower cellular concentrations.
- Split PROTACs allow for rapid assessment of various ligand combinations.
Conclusions:
- Oxime chemistry provides a viable route for creating split PROTACs.
- Pre-mixing PROTAC components enhances assembly efficiency.
- Split PROTACs offer a simplified approach for optimizing PROTAC molecules.
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