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@article{Craven:2018:10.1002/anie.201711825,
author = {Craven, G and Affron, D and Allen, C and Matthies, S and Greener, J and Morgan, R and Tate, E and Armstrong, A and Mann, D},
doi = {10.1002/anie.201711825},
journal = {Angewandte Chemie International Edition},
pages = {5257--5261},
title = {High-throughput kinetic analysis for target-directed covalent ligand discovery},
url = {http://dx.doi.org/10.1002/anie.201711825},
volume = {57},
year = {2018}
}
TY - JOUR
AB - 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 moleculesbased 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.
AU - Craven,G
AU - Affron,D
AU - Allen,C
AU - Matthies,S
AU - Greener,J
AU - Morgan,R
AU - Tate,E
AU - Armstrong,A
AU - Mann,D
DO - 10.1002/anie.201711825
EP - 5261
PY - 2018///
SN - 1433-7851
SP - 5257
TI - High-throughput kinetic analysis for target-directed covalent ligand discovery
T2 - Angewandte Chemie International Edition
UR - http://dx.doi.org/10.1002/anie.201711825
UR - https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201711825
UR - http://hdl.handle.net/10044/1/57267
VL - 57
ER -
Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ
e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821