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Proteolysis targeting chimeras (protein degraders) represent an innovative approach in drug discovery, leveraging bifunctional molecules to promote targeted protein degradation by linking target proteins to E3 ubiquitin ligases. Despite their promise, the development of protein degraders poses significant challenges:
Physicochemical Properties: Protein degraders, with molecular weights between 900-1,100 Da and increased polar surface area, often exhibit poor cell permeability, metabolic instability, and low oral bioavailability.
Optimization Complexity: Designing effective linkers and ligands requires balancing stability, solubility, and binding efficiency, while simultaneously enhancing PK and PD profiles.
At Creative Biogene, we provide comprehensive solutions to overcome these obstacles, offering expertise in ligand design, linker optimization, synthesis, and analytical characterization to accelerate your protein degrader research.
Effective protein degraders require high-quality ligands that specifically bind the target protein or the E3 ubiquitin ligase. Our ligand design services focus on optimizing binding affinity, molecular properties, and synthetic accessibility.
Design Strategy
| Structure-Based Design: |
| Integration of crystallographic data and protein-protein interaction analysis. |
| Optimization of binding interactions and linker attachment points. |
| Property Optimization: |
| Fine-tuning molecular weight, tPSA, and cLogP for better cell permeability. |
| Improving PK characteristics to enhance drug efficacy. |
| Selection Criteria: |
| High binding affinity, chemical stability, and degradation efficiency. |
Deliverables
Linker design is critical to achieving optimal protein degrader performance. The length, composition, and rigidity of the linker impact the molecule's solubility, permeability, and conformational flexibility.
Optimization Strategy
| Length and Composition |
| Determination of optimal linker length (15–25 atoms). |
| PEG chains for solubility or alkyl chains for hydrophobic interactions. |
| Incorporation of rigid elements (triazoles, alkynes) for structural control. |
| Attachment Site Selection |
| Crystal structure analysis for solvent-exposed attachment points. |
| Preservation of target protein and E3 ligase interactions. |
| Custom Chemistry |
| Tailored linkers, including PEG-based, alkyl chain, or hybrid designs, to suit specific project requirements. |
Translating computational designs into reality, our synthetic expertise brings protein degrader molecules from virtual conception to tangible compounds. Our integrated synthesis platform employs three strategic approaches - sequential synthesis, E3 ligand-first methodology, and convergent synthesis - to efficiently produce your designed candidates.
We utilize a modular stepwise approach to assemble protein degrader molecules, enabling precise control over individual components. This method is particularly effective for optimizing the chemical structures of target protein ligands and linkers.
Figure 1. Assembly from POI Ligands.
Key Features:
Precisely synthesizing initial fragments of target protein ligands and linkers.
Advantages:
With expertise in E3 ligand synthesis and functionalization, we prioritize the construction of stable E3 ligand-linker fragments before connecting them to target protein ligands.
Figure 2. Assembly from E3 Ligase Ligands.
Key Features:
Advantages:
We employ a parallel synthesis approach to prepare fragments of target protein ligands and E3 ligands, using high-efficiency click chemistry for final assembly. This strategy significantly improves synthesis efficiency and is ideal for creating protein degrader libraries.
Figure 3. Linker-Connected POI and E3 Ligands.
Key Features:
Advantages:
Why Choose Creative Biogene?
Get Started
Contact us today to discuss your protein degrader project. Whether you are exploring novel degrader molecules or optimizing existing designs, Creative Biogene is your trusted partner in advancing drug discovery. Take advantage of our free initial consultation to design a service package tailored to your needs.
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