2. Academic Validation
  3. Click chemistry enables preclinical evaluation of targeted epigenetic therapies

Click chemistry enables preclinical evaluation of targeted epigenetic therapies

  • Science. 2017 Jun 30;356(6345):1397-1401. doi: 10.1126/science.aal2066.
Dean S Tyler 1 2,  Johanna Vappiani 3,  Tatiana Cañeque 4 5 6,  Enid Y N Lam 1 2,  Aoife Ward 3,  Omer Gilan 1 2,  Yih-Chih Chan 1,  Antje Hienzsch 4 5 6,  Anna Rutkowska 3,  Thilo Werner 3,  Anne J Wagner 3,  Dave Lugo 7,  Richard Gregory 7,  Cesar Ramirez Molina 7,  Neil Garton 7,  Christopher R Wellaway 7,  Susan Jackson 1,  Laura MacPherson 1 2,  Margarida Figueiredo 1,  Sabine Stolzenburg 1,  Charles C Bell 1 2,  Colin House 1,  Sarah-Jane Dawson 1 2 8,  Edwin D Hawkins 9,  Gerard Drewes 3,  Rab K Prinjha 7,  Raphaël Rodriguez 4 5 6,  Paola Grandi 10,  Mark A Dawson 11 2 8 12
Affiliations

Affiliations

  • 1 Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
  • 3 Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.
  • 4 Chemical Cell Biology Group, Institut Curie, Paris Sciences et Lettres Research University, 26 Rue d'Ulm, 75248 Paris Cedex 05, France.
  • 5 CNRS UMR3666, 75005 Paris, France.
  • 6 INSERM U1143, 75005 Paris, France.
  • 7 Epigenetics Discovery Performance Unit, Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline, Stevenage, UK.
  • 8 Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia.
  • 9 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 10 Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany. paola.x.grandi@gsk.com mark.dawson@petermac.org.
  • 11 Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. paola.x.grandi@gsk.com mark.dawson@petermac.org.
  • 12 Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
PMID: 28619718 DOI: 10.1126/science.aal2066
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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