As a leading service provider in the field of biological research and drug discovery, Creative Biolabs is fully competent and dedicated to serving one-stop Proteolysis Targeting Chimeric (PROTAC^®) based molecular drug discovery which has become a promising strategy in the area of drug discovery. With the comprehensive advanced platform, Creative Biolabs provides global clients with PROTAC^® molecule discovery package service to meet the novel drug discovery goals. The package includes a variety of different services covering the whole process.

Introduction of PROTAC^®

Compared with traditional pharmaceutical drug discovery focused on directly controlling protein activity, PROTAC^® utilizes the proteasome-mediated proteolysis via E3 ligase and engage the body's housekeeping protein degradation system to selectively degrade the pathogenic proteins to treat cancer or other difficult-to-treat diseases. PROTAC^® is a heterobifunctional small molecule that consists of a linker and two warheads - one binds to the target protein, and the other recruits the E3 ligase (see Fig.1). Empowered by this bifunctional characteristic, the disease-causing proteins can be ubiquitinated and degraded by the proteasome which will result in a return to normal physiological tissue. It's emerging as a novel approach with potential to offer therapeutic interventions beyond the limitations of current existing approaches.

Fig.1 PROTAC^® recruitment of an E3 ligase for target protein degradation via the ubiquitin-proteasome pathway. (Corson, 2008)

Advantages of PROTAC^®

PROTAC^® has opened up a novel and exciting area of drug discovery because of the following advantages:

• Degrading pathogenic proteins rather than inhibiting them
• Low dosage
• Reduce toxicity
• Target undruggable proteins
• Prolonged pharmacodynamics effect

Our Molecule discovery Service Package

PROTAC^® is small molecule with a linker and two-headed molecules capable of degrading target proteins by inducing selective intracellular proteolysis. Our molecule discovery service package contains all aspects of the small molecules design, screening, optimization, and synthesis. In this way, an exquisitely potent PROTAC^® molecule with a high degree of degradation selectivity will be developed. We divide the package service into:

Ligand Design for Target Protein

Tagging of the target protein with ubiquitination is the key event prior to being removed by PROTAC^® molecule. Creative Biolabs offers ligand design service as well as available ligand products for proteins of interest. The ligand design may be inspired by the reported tight binding interaction, transient binding interaction, ubiquitination propensity of target protein or existing small molecule inhibitors.

Ligand Screening for E3 Ligase

E3 ligase can be recruited to tag the target protein for ubiquitination and degradation through the proteasome. Various E3 ligase binding moiety has been reported, and Creative Biolabs offers a comprehensive series of ligand screening service for E3 ligase. Customized design and ligand products are both available for our clients.

Linker Design and Optimization

The PROTAC^® linker connects two heads: a small peptide or molecule for E3 ubiquitin ligase recognition, and a ligand for target protein recognition. Creative Biolabs provides several types of linkers and also the optimization service. The length and position of the linker can be optimized for maximal interaction between target protein and E3 ligase to achieve efficient ubiquitination of the target protein and its ultimate degradation.

Fig. 2 PROTAC^® library possibilities.

PROTAC^® Structural Modification

The cell permeability and degree of degradation selectivity of PROTAC^® molecule can be optimized by structural modification or “mix and match” of variable linker-E3 ligase moiety combinations with specific target protein ligand. Creative Biolabs offers the structural modification service to assist our clients to get optimal PROTAC^® molecule.

Custom Peptide and Compound Synthesis

Once the PROTAC^® molecule design and optimization are confirmed, we are here to serve the custom peptide and compound synthesis for our clients if they are not in the products list. Creative Biolabs is committed to tailoring the molecule discovery service package to best fit your specific needs.

Highlight Features of Our Services

• Ph.D. level scientists and skillful technicians
• Extensive experience and advanced platforms
• High-quality one-stop service
• Superior after-sale service

Creative Biolabs offers our clients with various modules that cover every aspect of PROTAC^® service, from molecular discovery to biological evaluation. Any individual modules are available for our clients. To achieve the best efficacy, we do recommend our one-stop PROTAC^® service package, and we're committed to taking care of your project from scratch to full development. For more details regarding Creative Biolab's PROTAC^® service, please feel free to contact us to assist you.

Reference

1. Corson, TW., et al. Design and Applications of Bifunctional Small Molecules: Why Two Heads Are Better Than One. ACS Chem Biol. 2008, 3(11), 677-692.