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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}
}

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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  -

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