Targeted protein degradation

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Targeted protein degradation

Target Protein Degradation - Proteolysis Targeted Chimera (PROTAC)

INQUIRY

 

In mammalian cells, protein degradation is mainly carried out by the ubiquitin-proteasome system to dispose damaged or excess proteins. Ubiquitin can be attached to the substrate protein through a series of enzymatic reactions leading to the covalent bonding between the C-terminal glycine of ubiquitin and the lysine residue of the substrate. Ubiquitin-tagged proteins are eventually recognized and destructed by proteasome. In spite of the high complexity of ubiquitin system, it is not surprising that some components or processes in this system could provide for promising therapeutic targets to treat a variety of diseases, including cancer and neurodegeneration. One good example is the E3 ligases, which regulate the attachment of ubiquitin tags to the substrate protein for subsequent degradation.

 

Illustration of the PROTAC strategy

Illustration of the PROTAC strategy

 

Recently, Arvinas has developed a chemical strategy called Proteolysis Targeted Chimera (PROTAC) for E3 ligase-based degradation of target proteins.1 In principle, this method can be used to selectively degrade any protein of interest by bringing the target protein into proximity of the E3 ligase for proteasome-mediated proteolysis. Pioneered by Arvinas, PROTAC is becoming an promising strategy to target the so called "undruggable" proteins such as estrogen-related receptor alpha, cellular retinoic acid binding proteins, and BRD4.2 The key step of PROTAC is the construction a heterobifunctional small molecule that has two warheads – one binds to the target protein, and the other recruits the E3 ligase.

 

Target Protein Degradation - Proteolysis Targeting Chimera (PROTAC)

 

Profacgen, a leading biotech CRO, has been extensively working on bioconjugation services and assay development for more than a decade. Inspired by the discovery of PROTAC, we now offer small molecule-based conjugation services to help our customers develop a new class of therapeutic agents targeting cancers and other difficult-to-treat diseases. This degradation-oriented method is generally more advantageous than traditional enzyme inhibitory strategy in that PROTAC can:

 

Remove target proteins rather than blocking them;

Avoid using high dosage to achieve sufficient inhibition;

Reduce toxicity;

Degrade "uninhibitable" proteins.

Our services consist of different modules that cover every aspect of PROTAC development, from ligand identification to biological evaluation. Customers are encouraged to choose individual modules that best fit their needs. To achieve the best efficacy, we do recommend our one-stop service package that delivers unrivaled value and will take care of your research project from scratch to full development.

 

Target Protein Degradation - Proteolysis Targeting Chimera (PROTAC)Ligand identification

Affinity assays to confirm binding potency,

Structural modification, molecular docking.

 

 

Target Protein Degradation - Proteolysis Targeting Chimera (PROTAC)Chemical conjugation

Modification of ligands, linker development,

conjugation chemistry, full characterization.

Target Protein Degradation - Proteolysis Targeting Chimera (PROTAC)Biological evaluation

Enzyme inhibition, protein degradation, in vitro

ADME, in vivo tests on animal models.

For more information regarding Profacgen's PROTAC service, please contact us or call 1-631-448-8149. Our customer service representatives are available 24 hours a day, Monday through Friday, to assist you.

 

References:

1. Lai, A. C.; et al. Modular PROTAC Design for the Degradation of Oncogenic BCR‐ABL. Angew. Chem. Int. Ed. 2016, 55: 807-810.

2. Winter, G. E.; et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 2015, 348 (6241), 1376-1381.

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