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High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery
Gregory B Craven1,2, Dominic P Affron1, Charlotte E Allen1
1Department of Chemistry, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.
Angewandte Chemie (International Ed. in English)
|February 27, 2018
Summary
Quantitative irreversible tethering (qIT) identifies selective covalent ligands for biological targets. This method discovered a novel allosteric Cdk2 inhibitor, advancing drug discovery for cell cycle regulation.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Chemical Biology
Background:
- Cysteine-reactive small molecules serve as crucial chemical probes and therapeutic agents.
- Distinguishing selective covalent ligands from pan-reactive compounds necessitates rigorous kinetic analysis.
- Developing selective inhibitors is vital for targeted therapeutic applications.
Purpose of the Study:
- To introduce quantitative irreversible tethering (qIT) as a method for screening cysteine-reactive small molecules.
- To prospectively apply qIT for the discovery of covalent fragments targeting Cyclin-dependent kinase 2 (Cdk2).
- To validate the identified inhibitors through structural analysis and explore their therapeutic potential.
Main Methods:
- Development and application of quantitative irreversible tethering (qIT) for kinetic selectivity maximization.
- Prospective screening of cysteine-reactive small molecules against the cell cycle regulator Cdk2.
- X-ray crystallography to determine the structures of Cdk2-inhibitor complexes.
Main Results:
- Successful application of qIT to identify covalent fragments targeting Cdk2.
- Structural validation of the identified inhibitors, guiding further optimization efforts.
- Discovery of a Cdk2-selective allosteric (Type IV) kinase inhibitor with a novel mechanism.
Conclusions:
- Quantitative irreversible tethering (qIT) is a powerful technique for discovering selective covalent ligands.
- The identified Cdk2 inhibitor represents a promising lead for therapeutic development due to its novel allosteric mode-of-action.
- This approach holds significant potential for advancing drug discovery in oncology and other therapeutic areas.
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