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Multiparameter kinetic analysis for covalent fragment optimization using quantitative irreversible tethering (qIT)
File(s)
cbic.202000457.pdf (3.83 MB)
Published version
OA Location
Author(s)
Craven, Gregory Benedict
Affron, Dominic P
Kösel, Teresa
Wong, Tsz Lam M
Jukes, Zoë H
Type
Journal Article
Abstract
Covalent fragments are increasingly being implemented to develop chemical probes but the complex relationship between fragment structure and binding kinetics makes optimization uniquely challenging. We describe a new technique in covalent probe discovery that enables data driven optimization of covalent fragment potency and selectivity. This platform extends beyond the existing methods for covalent fragment hit identification by facilitating rapid multiparameter kinetic analysis of covalent structure-activity relationships through simultaneous determination of Ki, kinact and intrinsic reactivity. We apply this approach to develop novel probes against electrophile sensitive kinases and showcase how multiparameter kinetic analysis enabled a successful fragment merging strategy.
Date Issued
2020-07-13
Date Acceptance
2020-07-13
Citation
ChemBioChem: a European journal of chemical biology, 2020, 21 (23), pp.3417-3422
URI
URL
DOI
ISSN
1439-4227
Publisher
Wiley-VCH Verlag
Start Page
3417
End Page
3422
Journal / Book Title
ChemBioChem: a European journal of chemical biology
Volume
21
Issue
23
Copyright Statement
© 2020 The Authors. Published by Wiley-VCH GmbH.

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.
License URL
Sponsor
Cancer and Polio Research Fund Ltd
Engineering & Physical Science Research Council (E
Engineering & Physical Science Research Council (E
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32659037
Grant Number
NA
EP/R511547/1
Nil
Subjects
Cdk2
Covalent fragments
Electrophile-sensitive inhibition
Fragment-based drug discovery
Irreversible inhibition kinetics
Publication Status
Published
Coverage Spatial
Germany
Date Publish Online
2020-07-13