Identification and Selectivity Analysis of Protein Degrader Targets

In recent years, targeted protein degradation (TPD) has emerged as an innovative therapeutic strategy aiming to modulate disease by intervening in protein expression using drug molecules. Among these approaches, proteolysis targeting chimeras (PROTACs) have garnered significant attention. The concept of PROTAC was first proposed by Crews et al. in 2001, with the core idea being to leverage the endogenous ubiquitin-proteasome system to degrade target proteins, thereby achieving therapeutic goals. Due to their high activity, ability to target "undruggable" proteins, and overcoming drug resistance, PROTACs have become a hot topic in drug development, with major pharmaceutical companies such as Pfizer, Bayer, and Merck actively involved in research and development in this area.

In addition to PROTACs, there are several similar strategies, including molecular glue degraders utilizing the ubiquitin-proteasome system, lysosome targeting chimeras (LYTACs) utilizing the endosome-lysosome pathway, as well as autophagy targeting chimeras (AUTACs) and autophagosome tethering compounds (ATTECs) utilizing the autophagy-lysosome pathway. These approaches are paving the way for new avenues in disease treatment.

However, a key evaluation criterion in the development of such molecules is whether they can degrade target proteins specifically without affecting the abundance of other proteins in the cell. To achieve this goal, quantitative proteomics technology plays a crucial role. This technology enables quantitative comparison of the abundance of the same protein across different samples at the proteome level using high-resolution mass spectrometry. Currently, a commonly used quantitative proteomics strategy involves introducing stable isotope labels during peptide sample preparation. During mass spectrometry detection, peptides with the same amino acid sequence but from different samples exhibit different mass-to-charge ratios due to the difference in the mass of the isotope label. Therefore, the ratio of co-eluted ions of the same peptide sequence can quantitatively reflect the abundance of the same protein in different samples. This strategy not only improves the efficiency of sample preparation and mass spectrometry data acquisition but also reduces experimental errors between samples, making the results more stable and reliable.

Technical Platform

Chomix has developed a variety of quantitative chemical proteomics technology platforms. Its innovative platforms enable precise qualitative and quantitative analysis of over 5,000 proteins in a single cell line, providing robust support for comprehensive target selectivity analysis. Taking the example of the multi-quantitative proteomics technology platform based on Tandem Mass Tag (TMT) labeling, this technology first extracts the whole proteome from cell samples treated with protein degraders, and then processes them through enzymatic digestion and multi-quantitative labeling steps before being mixed together. To enhance the coverage depth of the proteome, liquid chromatography is typically utilized for pre-fractionation of peptide samples, followed by mass spectrometry detection of each peptide sample, thus deeply analyzing protein abundance differences between samples and elucidating crucial target information and selectivity data. This platform provides evaluation and guidance for the development and optimization of protein degraders.


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Project Identification and Selectivity Analysis of Protein Degrader Targets 
Sample Cell lysate, live cells
Hardware Platform Non-contact ultrasonic cell pulverizer,ChemiDoc MP Imaging System,Orbitrap Fusion Lumos Tribrid/Orbitrap Exploris 480/Q Exactive HF-X/timsTOF Pro 2 mass spectrometer
Project Duration 3-4 weeks
Deliverables Project Report (including experimental procedures, data analysis charts, bioinformatics analysis results)
Price Click to consult

Case Study

Project aim: Two PROTAC molecules were designed and synthesized. The on and off-target proteins need to be analyzed for comparison of selectivity.
Experimental method: TMT-based quantitative MS method was used for proteomic analysis.
Project results:


A total of 5900 proteins were quantified in tumor cell lines and ON & OFF targets were identified for PROTAC1 and 2 molecules (Orbitrap Exploris 480 mass spectrometer, TMT10plex and data analysis by PD 2.5)

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