Click chemistry enables preclinical evaluation of targeted epigenetic therapies.
Identifieur interne : 004991 ( Ncbi/Curation ); précédent : 004990; suivant : 004992Click chemistry enables preclinical evaluation of targeted epigenetic therapies.
Auteurs : Dean S. Tyler [Australie] ; Johanna Vappiani [Allemagne] ; Tatiana Ca Eque [France] ; Enid Y N. Lam [Australie] ; Aoife Ward [Allemagne] ; Omer Gilan [Australie] ; Yih-Chih Chan [Australie] ; Antje Hienzsch [France] ; Anna Rutkowska [Allemagne] ; Thilo Werner [Allemagne] ; Anne J. Wagner [Allemagne] ; Dave Lugo [Royaume-Uni] ; Richard Gregory [Royaume-Uni] ; Cesar Ramirez Molina [Royaume-Uni] ; Neil Garton [Royaume-Uni] ; Christopher R. Wellaway [Royaume-Uni] ; Susan Jackson [Australie] ; Laura Macpherson [Australie] ; Margarida Figueiredo [Australie] ; Sabine Stolzenburg [Australie] ; Charles C. Bell [Australie] ; Colin House [Australie] ; Sarah-Jane Dawson [Australie] ; Edwin D. Hawkins [Australie] ; Gerard Drewes [Allemagne] ; Rab K. Prinjha [Royaume-Uni] ; Raphaël Rodriguez [France] ; Paola Grandi [Allemagne] ; Mark A. Dawson [Australie]Source :
- Science (New York, N.Y.) [ 1095-9203 ] ; 2017.
Abstract
The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro and in vivo. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors. In our studies of mouse models of acute leukemia, we used high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments. We also demonstrate the differential distribution and effects of BET inhibitors in normal and malignant cells in vivo. This study provides a potential framework for the preclinical assessment of a wide range of drugs.
DOI: 10.1126/science.aal2066
PubMed: 28619718
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<author><name sortKey="Ramirez Molina, Cesar" sort="Ramirez Molina, Cesar" uniqKey="Ramirez Molina C" first="Cesar" last="Ramirez Molina">Cesar Ramirez Molina</name>
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<author><name sortKey="Garton, Neil" sort="Garton, Neil" uniqKey="Garton N" first="Neil" last="Garton">Neil Garton</name>
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<author><name sortKey="Wellaway, Christopher R" sort="Wellaway, Christopher R" uniqKey="Wellaway C" first="Christopher R" last="Wellaway">Christopher R. Wellaway</name>
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<author><name sortKey="Bell, Charles C" sort="Bell, Charles C" uniqKey="Bell C" first="Charles C" last="Bell">Charles C. Bell</name>
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<author><name sortKey="Dawson, Sarah Jane" sort="Dawson, Sarah Jane" uniqKey="Dawson S" first="Sarah-Jane" last="Dawson">Sarah-Jane Dawson</name>
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<author><name sortKey="Hawkins, Edwin D" sort="Hawkins, Edwin D" uniqKey="Hawkins E" first="Edwin D" last="Hawkins">Edwin D. Hawkins</name>
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<author><name sortKey="Drewes, Gerard" sort="Drewes, Gerard" uniqKey="Drewes G" first="Gerard" last="Drewes">Gerard Drewes</name>
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<author><name sortKey="Prinjha, Rab K" sort="Prinjha, Rab K" uniqKey="Prinjha R" first="Rab K" last="Prinjha">Rab K. Prinjha</name>
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<author><name sortKey="Rodriguez, Raphael" sort="Rodriguez, Raphael" uniqKey="Rodriguez R" first="Raphaël" last="Rodriguez">Raphaël Rodriguez</name>
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<author><name sortKey="Grandi, Paola" sort="Grandi, Paola" uniqKey="Grandi P" first="Paola" last="Grandi">Paola Grandi</name>
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<author><name sortKey="Dawson, Mark A" sort="Dawson, Mark A" uniqKey="Dawson M" first="Mark A" last="Dawson">Mark A. Dawson</name>
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<author><name sortKey="Chan, Yih Chih" sort="Chan, Yih Chih" uniqKey="Chan Y" first="Yih-Chih" last="Chan">Yih-Chih Chan</name>
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<author><name sortKey="Hienzsch, Antje" sort="Hienzsch, Antje" uniqKey="Hienzsch A" first="Antje" last="Hienzsch">Antje Hienzsch</name>
<affiliation wicri:level="1"><nlm:affiliation>Chemical Cell Biology Group, Institut Curie, Paris Sciences et Lettres Research University, 26 Rue d'Ulm, 75248 Paris Cedex 05, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Chemical Cell Biology Group, Institut Curie, Paris Sciences et Lettres Research University, 26 Rue d'Ulm, 75248 Paris Cedex 05</wicri:regionArea>
<wicri:noRegion>75248 Paris Cedex 05</wicri:noRegion>
<wicri:noRegion>75248 Paris Cedex 05</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Rutkowska, Anna" sort="Rutkowska, Anna" uniqKey="Rutkowska A" first="Anna" last="Rutkowska">Anna Rutkowska</name>
<affiliation wicri:level="3"><nlm:affiliation>Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg</wicri:regionArea>
<placeName><region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Karlsruhe</region>
<settlement type="city">Heidelberg</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Werner, Thilo" sort="Werner, Thilo" uniqKey="Werner T" first="Thilo" last="Werner">Thilo Werner</name>
<affiliation wicri:level="3"><nlm:affiliation>Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg</wicri:regionArea>
<placeName><region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Karlsruhe</region>
<settlement type="city">Heidelberg</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wagner, Anne J" sort="Wagner, Anne J" uniqKey="Wagner A" first="Anne J" last="Wagner">Anne J. Wagner</name>
<affiliation wicri:level="3"><nlm:affiliation>Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg</wicri:regionArea>
<placeName><region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Karlsruhe</region>
<settlement type="city">Heidelberg</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lugo, Dave" sort="Lugo, Dave" uniqKey="Lugo D" first="Dave" last="Lugo">Dave Lugo</name>
<affiliation wicri:level="1"><nlm:affiliation>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage</wicri:regionArea>
<wicri:noRegion>Stevenage</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Gregory, Richard" sort="Gregory, Richard" uniqKey="Gregory R" first="Richard" last="Gregory">Richard Gregory</name>
<affiliation wicri:level="1"><nlm:affiliation>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage</wicri:regionArea>
<wicri:noRegion>Stevenage</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ramirez Molina, Cesar" sort="Ramirez Molina, Cesar" uniqKey="Ramirez Molina C" first="Cesar" last="Ramirez Molina">Cesar Ramirez Molina</name>
<affiliation wicri:level="1"><nlm:affiliation>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage</wicri:regionArea>
<wicri:noRegion>Stevenage</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Garton, Neil" sort="Garton, Neil" uniqKey="Garton N" first="Neil" last="Garton">Neil Garton</name>
<affiliation wicri:level="1"><nlm:affiliation>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage</wicri:regionArea>
<wicri:noRegion>Stevenage</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wellaway, Christopher R" sort="Wellaway, Christopher R" uniqKey="Wellaway C" first="Christopher R" last="Wellaway">Christopher R. Wellaway</name>
<affiliation wicri:level="1"><nlm:affiliation>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage</wicri:regionArea>
<wicri:noRegion>Stevenage</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Jackson, Susan" sort="Jackson, Susan" uniqKey="Jackson S" first="Susan" last="Jackson">Susan Jackson</name>
<affiliation wicri:level="1"><nlm:affiliation>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria</wicri:regionArea>
<wicri:noRegion>Victoria</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Macpherson, Laura" sort="Macpherson, Laura" uniqKey="Macpherson L" first="Laura" last="Macpherson">Laura Macpherson</name>
<affiliation wicri:level="1"><nlm:affiliation>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria</wicri:regionArea>
<wicri:noRegion>Victoria</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Figueiredo, Margarida" sort="Figueiredo, Margarida" uniqKey="Figueiredo M" first="Margarida" last="Figueiredo">Margarida Figueiredo</name>
<affiliation wicri:level="1"><nlm:affiliation>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria</wicri:regionArea>
<wicri:noRegion>Victoria</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Stolzenburg, Sabine" sort="Stolzenburg, Sabine" uniqKey="Stolzenburg S" first="Sabine" last="Stolzenburg">Sabine Stolzenburg</name>
<affiliation wicri:level="1"><nlm:affiliation>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria</wicri:regionArea>
<wicri:noRegion>Victoria</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Bell, Charles C" sort="Bell, Charles C" uniqKey="Bell C" first="Charles C" last="Bell">Charles C. Bell</name>
<affiliation wicri:level="1"><nlm:affiliation>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria</wicri:regionArea>
<wicri:noRegion>Victoria</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="House, Colin" sort="House, Colin" uniqKey="House C" first="Colin" last="House">Colin House</name>
<affiliation wicri:level="1"><nlm:affiliation>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria</wicri:regionArea>
<wicri:noRegion>Victoria</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Dawson, Sarah Jane" sort="Dawson, Sarah Jane" uniqKey="Dawson S" first="Sarah-Jane" last="Dawson">Sarah-Jane Dawson</name>
<affiliation wicri:level="1"><nlm:affiliation>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria</wicri:regionArea>
<wicri:noRegion>Victoria</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hawkins, Edwin D" sort="Hawkins, Edwin D" uniqKey="Hawkins E" first="Edwin D" last="Hawkins">Edwin D. Hawkins</name>
<affiliation wicri:level="1"><nlm:affiliation>The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria</wicri:regionArea>
<wicri:noRegion>Victoria</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Drewes, Gerard" sort="Drewes, Gerard" uniqKey="Drewes G" first="Gerard" last="Drewes">Gerard Drewes</name>
<affiliation wicri:level="3"><nlm:affiliation>Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg</wicri:regionArea>
<placeName><region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Karlsruhe</region>
<settlement type="city">Heidelberg</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Prinjha, Rab K" sort="Prinjha, Rab K" uniqKey="Prinjha R" first="Rab K" last="Prinjha">Rab K. Prinjha</name>
<affiliation wicri:level="1"><nlm:affiliation>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage</wicri:regionArea>
<wicri:noRegion>Stevenage</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Rodriguez, Raphael" sort="Rodriguez, Raphael" uniqKey="Rodriguez R" first="Raphaël" last="Rodriguez">Raphaël Rodriguez</name>
<affiliation wicri:level="1"><nlm:affiliation>Chemical Cell Biology Group, Institut Curie, Paris Sciences et Lettres Research University, 26 Rue d'Ulm, 75248 Paris Cedex 05, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Chemical Cell Biology Group, Institut Curie, Paris Sciences et Lettres Research University, 26 Rue d'Ulm, 75248 Paris Cedex 05</wicri:regionArea>
<wicri:noRegion>75248 Paris Cedex 05</wicri:noRegion>
<wicri:noRegion>75248 Paris Cedex 05</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Grandi, Paola" sort="Grandi, Paola" uniqKey="Grandi P" first="Paola" last="Grandi">Paola Grandi</name>
<affiliation wicri:level="3"><nlm:affiliation>Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany. paola.x.grandi@gsk.com mark.dawson@petermac.org.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg</wicri:regionArea>
<placeName><region type="land" nuts="1">Bade-Wurtemberg</region>
<region type="district" nuts="2">District de Karlsruhe</region>
<settlement type="city">Heidelberg</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Dawson, Mark A" sort="Dawson, Mark A" uniqKey="Dawson M" first="Mark A" last="Dawson">Mark A. Dawson</name>
<affiliation wicri:level="1"><nlm:affiliation>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. paola.x.grandi@gsk.com mark.dawson@petermac.org.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria</wicri:regionArea>
<wicri:noRegion>Victoria</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">Science (New York, N.Y.)</title>
<idno type="eISSN">1095-9203</idno>
<imprint><date when="2017" type="published">2017</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en">The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro and in vivo. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors. In our studies of mouse models of acute leukemia, we used high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments. We also demonstrate the differential distribution and effects of BET inhibitors in normal and malignant cells in vivo. This study provides a potential framework for the preclinical assessment of a wide range of drugs.</div>
</front>
</TEI>
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