Quantitative Analysis of Occupancy and Selectivity of Covalent Small Molecule Drug Targets

Covalent drugs primarily exert their effects by forming covalent bonds with specific amino acid residues on target proteins, including cysteine, lysine, serine, among others. Aspirin was the first covalent drug molecule discovered, and several representative covalent drugs with anti-inflammatory bioactivity exist in natural products, such as artemisinin. In recent years, covalent targeted drugs have gained extensive attention from pharmaceutical companies. Currently, at least six covalent drugs targeting kinase targets have been FDA-approved, such as ibrutinib targeting the BTK kinase.

An effective approach for discovering covalent drug targets in cells or tissues is to chemically modify active small molecules by introducing reporter groups (such as biotin, bioorthogonal groups, etc.). While retaining the original activity of the small molecule, this modification allows us to directly capture the protein targets interacting with it in live cells or tissues. Subsequently, through enrichment, enzymatic digestion, mass spectrometry identification, and data analysis, omics information about the targets and amino acid residue information regarding the small molecule action can be obtained. However, in practical applications, many active molecules are not easily chemically modified, or the products produced after reacting with amino acid residues are unstable, making them unsuitable for mass spectrometry detection. In response to these challenges, SciCorpBio offers an effective solution - competitive site identification.

Technical Platform

Our technology platform is centered around a universal chemical probe. When an active small molecule reacts with an amino acid residue and occupies the binding site, this universal chemical probe generates a significant signal difference for that binding site compared to blank control samples. By detecting these differences in the labeling signals, we can accurately obtain information about the target proteins and amino acid residues of the active molecule, including both expected (on-target) and potential off-target proteins. This technology platform provides robust support for target discovery of covalent drugs and research into drug mechanisms of action.


Our Advantages

1. Technical Excellence: Experienced team, top-tier journal publications, and authoritative industry services.
2. Core Patent Technology: Exclusive patents and advanced hardware for early drug development support.
3. One-stop Service: Covering probe design, synthesis, target discovery, bioinformatics analysis, and timely progress feedback for customer satisfaction.
4. Rigorous Quality Management: ISO9001 certification ensures trustworthy and authentic reports.

Our Service

Project Quantitative Analysis of Occupancy and Selectivity of Covalent Small Molecule Drug Targets
Sample Pure protein, cell lysate, live cells, diseased tissue, blood, bacteria, plant tissue
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 2-4 weeks
Deliverables Project Report (including experimental procedures, data analysis charts, bioinformatics analysis results)
Price Click to consult

Case Study

AMG510, developed by Amgen, is the world's first targeted drug for KRAS-G12C mutant tumors. This project aims to verify its target specificity and selectivity in corresponding mutant cells. Using Chomix's DIA-ABPP platform, we comprehensively screened the covalent targets of AMG510 in cells down to the amino acid residue level.
Experimental data show that in four repeated experiments on NCI-H358 cells, a total of 16,992 cysteine residues from 5,768 proteins were systematically analyzed. Under 1μM AMG510 treatment, the KRAS_C12 site showed significant changes, while KRAS_C80 remained unaffected, providing strong evidence for the high specificity of AMG510 towards the KRAS-G12C mutant site (marked with an asterisk indicating the targeted cysteine residue site).



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