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High-throughput kinetic analysis for target-directed covalent ligand discovery

DOI: 10.1002/anie.201711825 DOI Help

Authors: Gregory B. Craven (Imperial College London) , Dominic P. Affron (Imperial College London) , Charlotte E. Allen (Imperial College London) , Stefan Matthies (Imperial College London) , Joe G. Greener (Imperial College London) , Rhodri M. L. Morgan (Imperial College London) , Edward W. Tate (Imperial College London) , Alan Armstrong (Imperial College London) , David J. Mann (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: February 2018
Diamond Proposal Number(s): 12579 , 17221

Open Access Open Access

Abstract: Cysteine-reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-reactive compounds. Here we describe quantitative irreversible tethering (qIT), a general method for screening cysteine-reactive small molecules based upon the maximization of kinetic selectivity. We apply this method prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-selective allosteric (type IV) kinase inhibitor whose novel mode-of-action could be exploited therapeutically.

Journal Keywords: Cdk2; Covalent inhibition; Fragment-based drug discovery; Kinetics; Protein modification

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 14/03/2018 10:28


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)