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Solutions for Targeted Protein Degradation

Targeted protein degradation (TPD) is a prospective therapeutic approach that uses the cell’s own destructive machinery to degrade proteins that cause disease, or drive disease progression. TPD is attractive as a therapeutic modality, because many proteins of interest (POIs) lack features (e.g., binding pockets) that can be targeted by traditional small molecule therapies rendering them “undruggable” using conventional methods. Protein degrader platforms like PROteolysis TArgeting Chimeras (PROTACs) and molecular glues represent a novel class of drugs (“degraders”) that utilize the ubiquitin-proteasome system (UPS) to initiate POI degradation, while platforms like autophagosome-tethering compounds (ATTECs), AUTOphagy-TArgeting Chimeras (AUTOTACs), AUtophagy-TArgeting Chimeras (AUTACs), antibody-based PROTACs (AbTACs), and LYsosome TArgeting Chimeras (LYTACs) utilize degraders that leverage the autophagosome or lysosome system to degrade POIs. These platforms, along with other TPD modalities, can target previously undruggable proteins for degradation by inducing proximity-based interactions between the POI and an effector molecule, opening the door to the potential development of targeted drug therapies for a wide range of diseases.

Scientists at Cell Signaling Technology have deep signaling expertise and can assist you with understanding the on- and off-target effects of your candidate target for TPD treatment. You can also access a broad catalog with a wide range of products, along with industry-leading proteomic services, that can help you streamline your degrader discovery workflow.

Targeted Protein Degradation (TPD) Products and Services

Click on each step in the diagram to learn more about specific CST workflow solutions that are available.

Diagram showing the steps in ubiquitin proteasome system-mediated TPD drug discovery

Ubiquitin proteasome system-mediated TPD drug discovery. (Step 1) Screen for degrader candidates that can bind to an E3 ligase and the target protein. (Step 2) Confirm that the degrader forms a ternary complex with the E3 ligase and target protein. (Step 3) Check for target protein polyubiquitination. (Step 4) Quantitate target degradation. (Step 5) Investigate on- and off-target effects to understand the phenotypic consequences of degrading the target protein.

Degrader Discovery

Degrader Discovery

You can identify the degrader and the associated E3 ubiquitin ligase for the target molecule in cells or tissues of interest using the following products.

  • E3 Ligase Antibodies: Specific antibodies recognizing E3 ligases or their components such as CRBN, VHL, KEAP1, and MDM2 are validated for your platform. Refer to the Ubiquitin Ligase Table for a list of E3 ubiquitin ligases and their known substrates.
  • Proteomics Analytical Services Profile key proteins and post-translational modifications to quickly ID potential targets and E3 ubiquitin ligases with the help of CST Proteomics Analytical Services. These services offer chemical-proteomics to identify reactive cysteines in complex proteomes for covalent-inhibitor drug development, allowing you to uncover novel cysteines that modulate protein function or help identify cellular targets susceptible to electrophilic warheads.
  • Cysteine Profiling: Map out reactive amino acid side chains on proteins of interest in the context of complex biological systems. Receive an optimized workflow solution using reactive cysteine labeling, along with peptide enrichment mass spectrometry analysis to efficiently identify and quantify accessible, reactive cysteine sites on important protein targets.

Ternary Complex Formation

Ternary Complex Formation

You can investigate ternary complex formation using assays designed to reveal protein-protein interactions. Examples include TR-FRET, co-immunoprecipitation, or AlphaLISA, which use target-specific antibodies to demonstrate physical proximity between an E3 ligase and your target protein. Optimal ternary complex formation is essential for efficient ubiquitination of the POI, and is necessary for efficient UPS-mediated degradation.

CST offers validated and reproducible off-the-shelf solutions, including tagged antibodies and matched antibody pairs, to support ternary complex formation experiments. Don’t see the conjugation or formulation you need for your platform? CST can develop, optimize, and validate it for you.

  • Custom Conjugation Services: CST has highly experienced custom conjugation experts that you can lean on. If you don’t see the conjugated antibody you need for your platform in our catalog, we’ll conjugate it to a metal, fluorophore, biotin, DIG, and other tags for you. Review the Resources and Guides for Antibodies Compatible with Your Assay Platform to find the conjugation that will work for your platform.
  • Matched Antibody Pairs: Carrier-free, conjugation-ready Matched Antibody Pairs have been optimized for you and are ready for your TR-FRET assays.
  • Customized Formulations for Immunoassay Development: Order BSA-, azide-, and glycerol-free antibody formulations for your ELISA-like assays and in vivo functional assay development.
  • Anti-Tag Antibodies: Pull down transfected, recombinant tagged proteins in co-immunoprecipitation experiments with specific, sensitive CST® tagged antibodies.
  • Proteomics Analytical Services: Qualitatively and quantitatively profile proteins in your sample. CST scientists can perform tandem mass tag (TMT) assays to assess protein-protein interactions and Proximity Labeling (TurboID/BioID) to confirm ternary complex formation for you.

Target Ubiquitination

Target Ubiquitination

You can confirm the ubiquitination of your target protein with CST proteostasis antibodies, or obtain a comprehensive view of all ubiquitination sites on your target protein using either a PTMScan® Ubiquitin kit or by utilizing CST Proteomic Analytical Services.

Target Degradation

Target Degradation

You can evaluate the effectiveness of your degrader candidates by directly assaying levels of your target protein after treatment by using specific and sensitive antibodies available from CST.

Application-validated antibodies for, but not limited to:

 

You can find high-quality antibodies against your target of interest that have been validated and approved for use in the following applications:

Additionally, off-the-shelf or customized carrier-free antibodies are available for high-throughput pair-based assay platforms. Need a specific conjugation for your platform? Custom conjugation services are also available.

If you are targeting a mutant version of a protein such as EGFR, search through the CST catalog of mutant-specific antibodies. Don't see the protein mutation you are looking for? Contact us for more information!

On/Off Target Effect

On/Off Target Effect

Get a broad molecular understanding of the off-target effects of your TPD molecule by utilizing CST Proteomics Analytical Services.

Work with a CST scientist to perform the following:

  • Proteomics Discovery Services:
    • PTMScan Discovery Proteomic Services: Depending on your target of interest, perform a comprehensive PTM analysis for ubiquitinated, phosphorylated, acetylated, and methylated proteins in your sample to monitor the downstream effects of a TPD molecule.
    • KinomeView® Service: Identify areas of the kinome that are modulated upon TPD molecule treatment when targeting a kinase.
  • Total Proteomic Profiling:
    • Gain insight into the downstream effects of a TPD molecule and determine potency with time-course studies.
    • Understand the on-target specificity of a TPD molecule and off-target cross reactivity.
  • UbiScan–Ubiquitination Proteomics: Quantitatively profile thousands of non-redundant ubiquitinated sequences with LC-MS/MS to identify off-target proteins being undesirably targeted for proteasomal degradation.

Or use one of the following CST kits:

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