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High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery

Craven, GB; Affron, DP; Allen, CE; Matthies, S; Greener, JG; Morgan, RML; Tate, EW; ... Mann, DJ; + view all (2018) High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery. Angewandte Chemie - International Edition , 57 (19) pp. 5257-5261. 10.1002/anie.201711825. Green open access

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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. Quantitative irreversible tethering (qIT), a general method for screening cysteine-reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied 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.

Type: Article
Title: High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/anie.201711825
Publisher version: https://doi.org/10.1002/anie.201711825
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Computer Science
URI: https://discovery.ucl.ac.uk/id/eprint/10059988
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