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High‐Throughput Kinetic Analysis for Target‐Directed Covalent Ligand Discovery
Author(s) -
Craven Gregory B.,
Affron Dominic P.,
Allen Charlotte E.,
Matthies Stefan,
Greener Joe G.,
Morgan Rhodri M. L.,
Tate Edward W.,
Armstrong Alan,
Mann David J.
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201711825
Subject(s) - covalent bond , chemistry , allosteric regulation , small molecule , cysteine , combinatorial chemistry , ligand (biochemistry) , molecule , high throughput screening , stereochemistry , enzyme , biochemistry , organic chemistry , receptor
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.