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An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine‐56

The stress‐inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its en...

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Detalles Bibliográficos
Autores principales: Pettinger, Jonathan, Le Bihan, Yann‐Vaï, Widya, Marcella, van Montfort, Rob L. M., Jones, Keith, Cheeseman, Matthew D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412842/
https://www.ncbi.nlm.nih.gov/pubmed/28225177
http://dx.doi.org/10.1002/anie.201611907
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author Pettinger, Jonathan
Le Bihan, Yann‐Vaï
Widya, Marcella
van Montfort, Rob L. M.
Jones, Keith
Cheeseman, Matthew D.
author_facet Pettinger, Jonathan
Le Bihan, Yann‐Vaï
Widya, Marcella
van Montfort, Rob L. M.
Jones, Keith
Cheeseman, Matthew D.
author_sort Pettinger, Jonathan
collection PubMed
description The stress‐inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine‐targeted irreversible inhibitor. Using rational design, we adapted a validated 8‐N‐benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition. However, no cysteine in the protein was modified; instead, we demonstrate that lysine‐56 is the key nucleophilic residue. Targeting this lysine could lead to a new design paradigm for HSP72 chemical probes and drugs.
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spelling pubmed-54128422017-05-15 An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine‐56 Pettinger, Jonathan Le Bihan, Yann‐Vaï Widya, Marcella van Montfort, Rob L. M. Jones, Keith Cheeseman, Matthew D. Angew Chem Int Ed Engl Communications The stress‐inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine‐targeted irreversible inhibitor. Using rational design, we adapted a validated 8‐N‐benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition. However, no cysteine in the protein was modified; instead, we demonstrate that lysine‐56 is the key nucleophilic residue. Targeting this lysine could lead to a new design paradigm for HSP72 chemical probes and drugs. John Wiley and Sons Inc. 2017-02-22 2017-03-20 /pmc/articles/PMC5412842/ /pubmed/28225177 http://dx.doi.org/10.1002/anie.201611907 Text en © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Communications
Pettinger, Jonathan
Le Bihan, Yann‐Vaï
Widya, Marcella
van Montfort, Rob L. M.
Jones, Keith
Cheeseman, Matthew D.
An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine‐56
title An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine‐56
title_full An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine‐56
title_fullStr An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine‐56
title_full_unstemmed An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine‐56
title_short An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine‐56
title_sort irreversible inhibitor of hsp72 that unexpectedly targets lysine‐56
topic Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412842/
https://www.ncbi.nlm.nih.gov/pubmed/28225177
http://dx.doi.org/10.1002/anie.201611907
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