Click chemistry enables preclinical evaluation of targeted epigenetic therapies
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...
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| Published in | Science (American Association for the Advancement of Science) Vol. 356; no. 6345; pp. 1397 - 1401 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Association for the Advancement of Science
30.06.2017
The American Association for the Advancement of Science American Association for the Advancement of Science (AAAS) |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0036-8075 1095-9203 1095-9203 |
| DOI | 10.1126/science.aal2066 |
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| 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. |
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| AbstractList | Drugs that show promise in preclinical models often fail in the clinic, in part because of limited information on drug localization within cells and across tissues. In a proof-of-concept study, Tyler et al. applied click chemistry methods to study the localization of bromodomain inhibitors. These are cancer drugs that alter chromatin structure and gene expression. Clickable derivatives of the drugs localized within chromatin and showed that the drugs exhibit distinct modes of binding at responsive and unresponsive genes. In a mouse leukemia model, the click-probes revealed that the drugs accumulate to different extents in the spleen and bone marrow, which are two tissue sources of leukemic cells.Science, this issue p. 1397 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. 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. Are better drugs just a click away? Drugs that show promise in preclinical models often fail in the clinic, in part because of limited information on drug localization within cells and across tissues. In a proof-of-concept study, Tyler et al. applied click chemistry methods to study the localization of bromodomain inhibitors. These are cancer drugs that alter chromatin structure and gene expression. Clickable derivatives of the drugs localized within chromatin and showed that the drugs exhibit distinct modes of binding at responsive and unresponsive genes. In a mouse leukemia model, the click-probes revealed that the drugs accumulate to different extents in the spleen and bone marrow, which are two tissue sources of leukemic cells. Science , this issue p. 1397 Are better drugs just a click away?Drugs that show promise in preclinical models often fail in the clinic, in part because of limited information on drug localization within cells and across tissues. In a proof-of-concept study, Tyler et al. applied click chemistry methods to study the localization of bromodomain inhibitors. These are cancer drugs that alter chromatin structure and gene expression. Clickable derivatives of the drugs localized within chromatin and showed that the drugs exhibit distinct modes of binding at responsive and unresponsive genes. In a mouse leukemia model, the click-probes revealed that the drugs accumulate to different extents in the spleen and bone marrow, which are two tissue sources of leukemic cells.Science, this issue p. 1397 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. Drugs that show promise in preclinical models often fail in the clinic, in part because of limited information on drug localization within cells and across tissues. In a proof-of-concept study, Tyler et al. applied click chemistry methods to study the localization of bromodomain inhibitors. These are cancer drugs that alter chromatin structure and gene expression. Clickable derivatives of the drugs localized within chromatin and showed that the drugs exhibit distinct modes of binding at responsive and unresponsive genes. In a mouse leukemia model, the click-probes revealed that the drugs accumulate to different extents in the spleen and bone marrow, which are two tissue sources of leukemic cells. Science , this issue p. 1397 Conversion of an epigenetic drug into a probe amenable to click chemistry allows visualization of the drug’s activity in vivo. 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. 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.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. |
| Author | House, Colin Prinjha, Rab K. Cañeque, Tatiana Tyler, Dean S. Bell, Charles C. Rutkowska, Anna Dawson, Sarah-Jane Gilan, Omer Stolzenburg, Sabine Grandi, Paola Vappiani, Johanna Molina, Cesar Ramirez Hawkins, Edwin D. Drewes, Gerard Lugo, Dave Werner, Thilo Wagner, Anne J. Chan, Yih-Chih Figueiredo, Margarida Dawson, Mark A. Lam, Enid Y. N. Rodriguez, Raphaël Hienzsch, Antje Gregory, Richard Garton, Neil Ward, Aoife Jackson, Susan Wellaway, Christopher R. MacPherson, Laura |
| AuthorAffiliation | 9 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia 8 Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia 1 Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 4 Chemical Cell Biology Group, Institut Curie, Paris Sciences et Lettres Research University, 26 Rue d’Ulm, 75248 Paris Cedex 05, France 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia 6 INSERM U1143, 75005 Paris, France 5 CNRS UMR3666, 75005 Paris, France 7 Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK 10 Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia 3 Cellzome, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany |
| AuthorAffiliation_xml | – name: 6 INSERM U1143, 75005 Paris, France – name: 1 Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia – name: 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia – name: 8 Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia – name: 5 CNRS UMR3666, 75005 Paris, France – name: 7 Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK – name: 9 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia – name: 3 Cellzome, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany – name: 4 Chemical Cell Biology Group, Institut Curie, Paris Sciences et Lettres Research University, 26 Rue d’Ulm, 75248 Paris Cedex 05, France – name: 10 Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia |
| Author_xml | – sequence: 1 givenname: Dean S. surname: Tyler fullname: Tyler, Dean S. – sequence: 2 givenname: Johanna surname: Vappiani fullname: Vappiani, Johanna – sequence: 3 givenname: Tatiana surname: Cañeque fullname: Cañeque, Tatiana – sequence: 4 givenname: Enid Y. N. surname: Lam fullname: Lam, Enid Y. N. – sequence: 5 givenname: Aoife surname: Ward fullname: Ward, Aoife – sequence: 6 givenname: Omer surname: Gilan fullname: Gilan, Omer – sequence: 7 givenname: Yih-Chih surname: Chan fullname: Chan, Yih-Chih – sequence: 8 givenname: Antje surname: Hienzsch fullname: Hienzsch, Antje – sequence: 9 givenname: Anna surname: Rutkowska fullname: Rutkowska, Anna – sequence: 10 givenname: Thilo surname: Werner fullname: Werner, Thilo – sequence: 11 givenname: Anne J. surname: Wagner fullname: Wagner, Anne J. – sequence: 12 givenname: Dave surname: Lugo fullname: Lugo, Dave – sequence: 13 givenname: Richard surname: Gregory fullname: Gregory, Richard – sequence: 14 givenname: Cesar Ramirez surname: Molina fullname: Molina, Cesar Ramirez – sequence: 15 givenname: Neil surname: Garton fullname: Garton, Neil – sequence: 16 givenname: Christopher R. surname: Wellaway fullname: Wellaway, Christopher R. – sequence: 17 givenname: Susan surname: Jackson fullname: Jackson, Susan – sequence: 18 givenname: Laura surname: MacPherson fullname: MacPherson, Laura – sequence: 19 givenname: Margarida surname: Figueiredo fullname: Figueiredo, Margarida – sequence: 20 givenname: Sabine surname: Stolzenburg fullname: Stolzenburg, Sabine – sequence: 21 givenname: Charles C. surname: Bell fullname: Bell, Charles C. – sequence: 22 givenname: Colin surname: House fullname: House, Colin – sequence: 23 givenname: Sarah-Jane surname: Dawson fullname: Dawson, Sarah-Jane – sequence: 24 givenname: Edwin D. surname: Hawkins fullname: Hawkins, Edwin D. – sequence: 25 givenname: Gerard surname: Drewes fullname: Drewes, Gerard – sequence: 26 givenname: Rab K. surname: Prinjha fullname: Prinjha, Rab K. – sequence: 27 givenname: Raphaël surname: Rodriguez fullname: Rodriguez, Raphaël – sequence: 28 givenname: Paola surname: Grandi fullname: Grandi, Paola – sequence: 29 givenname: Mark A. surname: Dawson fullname: Dawson, Mark A. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28619718$$D View this record in MEDLINE/PubMed https://hal.science/hal-04034188$$DView record in HAL |
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| ContentType | Journal Article |
| Copyright | Copyright © 2017 by the American Association for the Advancement of Science Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution 4.0 International License |
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| DOI | 10.1126/science.aal2066 |
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| Snippet | The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an... Drugs that show promise in preclinical models often fail in the clinic, in part because of limited information on drug localization within cells and across... Are better drugs just a click away?Drugs that show promise in preclinical models often fail in the clinic, in part because of limited information on drug... Are better drugs just a click away? Drugs that show promise in preclinical models often fail in the clinic, in part because of limited information on drug... |
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| SubjectTerms | Animal models Animals Benzodiazepines - pharmacology Benzodiazepines - therapeutic use Bone marrow Cancer Cells, Cultured Chemical Sciences Chemical synthesis Chemistry Chromatin Click Chemistry Compartments Cytometry Differential distribution Disease Models, Animal Drug Delivery Systems Drugs Epigenetics Epigenomics Flow cytometry Gene expression Gene sequencing Genes Heterogeneity In vivo methods and tests Inhibitors Leukemia Leukemia - drug therapy Leukemia - pathology Leukemias Life Sciences Localization Mice Narcotics Organic Chemistry Position (location) Precision Medicine Probes Proteomics Spleen Synthesis (chemistry) Therapy Tissue Distribution Transcription Transcription Factors - antagonists & inhibitors Tumor cells |
| Title | Click chemistry enables preclinical evaluation of targeted epigenetic therapies |
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