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

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Title: High-throughput kinetic analysis for target-directed covalent ligand discovery
Authors: Craven, G
Affron, D
Allen, C
Matthies, S
Greener, J
Morgan, R
Tate, E
Armstrong, A
Mann, D
Item Type: Journal Article
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 g uide 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.
Issue Date: 4-May-2018
Date of Acceptance: 16-Feb-2018
URI: http://hdl.handle.net/10044/1/57267
DOI: https://dx.doi.org/10.1002/anie.201711825
ISSN: 1521-3757
Publisher: Wiley
Start Page: 5257
End Page: 5261
Journal / Book Title: Angewandte Chemie
Volume: 57
Issue: 19
Copyright Statement: © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Cancer and Polio Research Fund Ltd
Funder's Grant Number: NA
Keywords: Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Chemistry
Cdk2
covalent inhibition
fragment-based drug discovery
kinetics
protein modification
DRUG DISCOVERY
IRREVERSIBLE INHIBITORS
BINDING FRAGMENTS
PROTEIN-KINASES
CANCER-THERAPY
ASSAY
BIOLOGY
DESIGN
THIOLS
PROBES
Cdk2
covalent inhibition
fragment-based drug discovery
kinetics
protein modification
03 Chemical Sciences
Organic Chemistry
Publication Status: Published
Online Publication Date: 2018-02-26
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences



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