Application Note | April 5, 2024

Protein Degrader Proteomics for PROTACs and Molecular Glues

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Proteolysis Targeting Chimeras (PROTACs) and molecular glues are novel classes of therapeutic agents with potential to transform the treatment landscape for cancer by finally targeting previously ‘undruggable’ proteins. They work by recruiting E3 ligases into close contact with the target protein for targeted degradation.

Discovery proteomics for PROTACs and molecular glues can help elucidate how these protein degraders interact with their target proteins and the ubiquitin-proteasome system. Analyses can span from broad cellular-based drug screenings of degrader molecules, assessing their selectivity toward a target of interest, to deep profiling of the global proteome for selected degraders to identify potential off-target effects. Understanding the intricate interplay and mechanisms underlying PROTAC and molecular glue action is critical to identify novel targets and for optimizing drug efficacy and safety.

See how Sapient’s mass spectrometry-based Protein Degrader Proteomics provides a discovery proteomics approach to explore PROTAC-proteome and molecular glue-proteome interactions with scalable throughput and coverage depth that is specifically aligned to support development of these innovative therapeutics.

Download the Application Note to learn the technical details of our method and how it can be tailored for high throughput cell-based screening via /HT/ Protein Degrader Proteomics or deep global proteome profiling via /Deep/ Protein Degrader Proteomics.

Our /HT/ workflow allows for rapid screening of tens of thousands of compounds for their selectivity and specificity towards a protein target of interest. The short, 5-minute gradient workflow measures >5,000 proteins and post-translational modifications (PTMs) per cellular sample and can be used to process thousands of samples per day.

The /Deep/ workflow measures the abundance of >10,000 proteins and PTMs in as little as 20ug protein lysates. This approach is amenable to deeply profile selected or pre-screened protein degraders across different cell lines, drugs, doses, and time points with high accuracy and precision.

Using stable isotope labeling by amino acids (SILAC) approaches, Sapient can also provide estimation of protein half life, including turnover and resynthesis kinetics, which is central to the design and development of protein degraders.

Additionally, Sapient’s proteomics for PROTACs and molecular glues can be used to monitor for changes in the cellular proteome in longitudinal samples to elucidate cellular mechanisms contributing to development of resistance or adverse events in patient populations over time. This allows for the careful selection of clinically relevant degrader agents, and empowers you with data to optimize drug efficacy, minimize toxicity, and overcome resistance mechanisms.

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