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Protein Degrader Service

Protein Degrader Discovery and Screening Services
Protein Degrader Design and Synthesis Services
Protein Degrader Process Development and Manufacturing
Protein Degrader Assessment and Validation Services
OverviewAdvantageMilestoneChallengeCapabilityServiceManagement

Traditional targeted therapies rely on small-molecule inhibitors that bind to proteins and block their functions. However, this "occupancy-driven" mechanism often suffers from issues such as off-target effects, insufficient selectivity, and drug resistance. Proteolysis-targeting chimeras (protein degraders) offer a groundbreaking alternative by inducing protein degradation instead of merely inhibiting their functions. This innovative approach has emerged as an up-and-coming technology in drug discovery, providing more targeted and effective therapeutic solutions.

What is Protein Degrader?

Protein degraders (Proteolysis-Targeting Chimeras) are bifunctional small molecules designed to degrade specific target proteins. These molecules consist of three key components:

mechanism of protein degraders.

  • Target Protein Ligand (warhead): A molecular component that binds to the protein of interest (POI) with high affinity and selectivity.
  • E3 Ligase Ligand: A molecule that recruits an E3 ubiquitin ligase, facilitating the ubiquitination of the target protein. Common E3 ligase ligands target VHL, CRBN, MDM2, and IAP.
  • Linker: A chemical moiety connecting the two ligands, which ensures proper molecular flexibility and stability while promoting the formation of a ternary complex.

The mechanism of protein degraders involves:

1. Binding to the target protein and E3 ligase to form a ternary complex.

2. The E3 ligase ubiquitinates the target protein, marking it for degradation.

This figure illustrates the mechanism of protein degraders.

3. The 26S proteasome degrades the ubiquitinated protein, while the protein degrader molecule remains available for repeated use.

This "one-to-many" mode of action differentiates protein degraders from traditional small-molecule inhibitors, which rely on a "one-to-one" relationship with their target proteins.

Advantages of Protein Degraders

  • Expanding Druggable Targets: Protein degraders can target proteins previously considered "undruggable," such as scaffold proteins and transcription factors. Protein degraders operate through a catalytic degradation mechanism that does not require permanent occupancy of active sites.
  • Catalytic Efficiency: A single protein degrader molecule can degrade multiple target proteins, reducing the need for high drug concentrations and minimizing off-target effects.
  • Overcoming Drug Resistance: By degrading the entire target protein, protein degraders can bypass resistance mechanisms arising from mutations in active sites.
  • Reducing Toxic Aggregates: Protein degraders remove dysfunctional proteins, preventing the formation of toxic aggregates, which is particularly beneficial for neurodegenerative diseases like Alzheimer's and Parkinson's.
  • Selective E3 Ligase Targeting: The ability to recruit specific E3 ligases enhances selectivity and safety.
  • Low Dosage Requirements: Due to their catalytic action, protein degraders are effective at low doses, reducing side effects and improving therapeutic outcomes.

Key Technological Milestones

Since protein degrader technology was first introduced by Crews and Deshaies in 2001, it has rapidly evolved. Early first-generation protein degraders faced limitations in cell permeability and pharmacokinetics. However, advancements in E3 ligase ligands and linker design have led to the development of second-generation protein degraders with enhanced activity and clinical potential. Several companies, including Arvinas, C4 Therapeutics, and Kymera Therapeutics, have spearheaded protein degrader research. Notable clinical candidates include:

CompanyDegrader TargetIndicationsE3 Ligase
ArvinasARV-110Prostate cancerCRBN
Arvinas/PfizerARV-471Breast cancerCRBN
Accutar BiotechAC682Breast cancerCRBN
ArvinasARV-766Prostate cancerCRBN
Bristol Myers SquibbCC-94676Prostate cancerCRBN
Dialectic TherapeuticsDT2216Liquid and solid tumorsVHL
Foghorn TherapeuticsFHD-609Synovial sarcomaCRBN
Kymera/SanofiKT-474Autoimmune diseases (e.g., AD, HS, RA)IRAK4
KymeraKT-413Autoimmune diseases (e.g., AD, HS, RA)IRAK4
KymeraKT-333Autoimmune diseases (e.g., AD, HS, RA)IRAK4
Nurix TherapeuticsNX-2127Liquid and solid tumorsCRBN
Nurix TherapeuticsNX-5948Liquid and solid tumorsCRBN
C4 TherapeuticsCFT-8634B cell malignanciesCRBN
C4 TherapeuticsCFT-8919B cell malignancies and autoimmune diseasesCRBN
C4 TherapeuticsCFT7455Synovial sarcomaCRBN
CullgenCG001419Cancer and other indicationsCRBN

Challenges in Protein Degrader Drug Development

Although protein degrader offers unique advantages over other drug discovery paradigms, it also has certain drawbacks that present significant challenges and issues:

  • Complex Drug Properties: Protein degraders are metabolically less stable and often exceed the molecular weight limits of Lipinski's "Rule of Five", leading to poor permeability, solubility, and oral bioavailability. Addressing these issues is crucial for their success.
  • Resistance: Genomic changes in E3 ligases, such as reduced CRBN or CUL2 expression, can lead to resistance. Limited use of E3 ligases in current designs also restricts protein degrader applications, emphasizing the need to explore more ligase types.
  • Hook and Off-Target Effects: The Hook Effect, where excessive protein degrader concentrations lower degradation efficiency, and off-target effects causing unintended protein degradation, pose significant challenges. For example, thalidomide derivatives degrade transcription factors like IKZF1 and GSTP1 due to "molecular glue" effects.
  • Target Selection: While protein degraders can potentially address "undruggable" targets, most current applications focus on traditional druggable proteins, limiting their broader impact.

Creative Biogene's Protein Degrader Development and Manufacturing Services

Creative Biogene provides end-to-end solutions for protein degrader drug development, addressing industry challenges with cutting-edge technology and expertise. Our comprehensive platform integrates molecular design, compound synthesis, and biological evaluation to deliver seamless R&D services.

Platform Capabilities

1 Smart Molecular Design Platform

  • Computer-Aided Drug Design (CADD)
  • Artificial Intelligence-Assisted Design (AIDD)
  • Structure-Based Optimization
  • Linker Design and Optimization

2 Extensive Compound Libraries

  • 100+ E3 ligase ligands
  • 550+ target protein ligands
  • 2,500+ linker structures
  • 6,000+ protein degrader molecules

3 Synthesis and Manufacturing Platform

  • Small molecule synthesis
  • Protein degrader molecule synthesis
  • Process development and optimization
  • Scale-up production
  • GMP manufacturing

4 Biological Evaluation Platform

  • Protein expression and purification
  • Binding activity assays
  • Degradation efficiency evaluation
  • Cell-based functional assays
  • Animal model studies

Detailed Services

Protein Degrader Discovery and Screening Services

We provide high-throughput screening for target protein ligands, E3 ligase ligands, and protein degrader linkers. Our platform supports precise ligand screening, particularly for E3 ligases such as MDM2, cIAP, VHL, and CRBN.

Protein Degrader Design and Synthesis Services

  • E3 Ligase Ligand Design: Advanced CADD and AIDD techniques to optimize ligand affinity.
  • Linker Optimization: Strategies to ensure intracellular stability and pharmacological activity.
  • Target Protein-Ligand Design: Customized designs for high selectivity and affinity.

Protein Degrader Assessment and Validation Services

  • Efficacy Evaluation: Cell and animal model studies to validate degradation efficiency.
  • DMPK Analysis: Comprehensive pharmacokinetics studies for molecule optimization.
  • Ternary Complex Analysis: In vitro and in vivo assays to assess stability and efficiency.

Protein Degrader Process Development and Manufacturing

  • Innovative Synthesis Routes: Cost-efficient production processes.
  • Scale-Up and GMP Production: From lab-scale to clinical-grade manufacturing.
  • Quality Control: Rigorous testing to ensure compliance with industry standards.

Project and Data Management

Overcoming the unique challenges of protein degrader drug discovery requires expert coordination and strategic planning. We ensure:

  • Integrated Collaboration: Seamless alignment of chemistry, biology, and ADME/DMPK activities to drive progress.
  • Proactive Management: Clear milestones and early risk identification for timely, adaptable delivery.
  • Transparent Updates: Regular, actionable insights keep you informed and engaged.
  • Data-Driven Decisions: Real-time data access supports informed prioritization and continuous progress.

Partner with Creative Biogene for innovative, high-quality protein degrader drug development solutions. We are committed to advancing your research and achieving your therapeutic goals.

* For research use only. Not intended for any clinical use.
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