Journal article

Click chemistry enables preclinical evaluation of targeted epigenetic therapies

Dean S Tyler, Johanna Vappiani, Tatiana Caneque, Enid YN Lam, Aoife Ward, Omer Gilan, Yih-Chih Chan, Antje Hienzsch, Anna Rutkowska, Thilo Werner, Anne J Wagner, Dave Lugo, Richard Gregory, Cesar Ramirez Molina, Neil Garton, Christopher R Wellaway, Susan Jackson, Laura MacPherson, Margarida Figueiredo, Sabine Stolzenburg Show all



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 differe..

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Awarded by National Health and Medical Research Council of Australia

Awarded by European Union

Awarded by European Research Council under the European Union's Horizon 2020 research and innovation program

Funding Acknowledgements

Work in the Dawson laboratory is supported by the National Health and Medical Research Council of Australia (grants 1106444, 1085015, and 1106447 to M.A.D.). M.A.D. is currently supported by a Senior Leukaemia Foundation Australia Fellowship and a VESKI Innovation Fellowship. D.S.T. and O.G. are respectively supported by a Ph.D. scholarship and a postdoctoral fellowship from Leukaemia Foundation Australia. E.Y.N.L. and L.M. are supported by fellowships from the Victoria Cancer Agency. Work performed at Cellzome was supported in part by funding from the European Union (FP7 Project BLUEPRINT/282510). We thank V. Benes and the European Molecular Biology Laboratory GeneCore facility for DNA sequencing. Research in the Rodriguez laboratory is supported by the Emergence Ville de Paris Program and funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement 647973). Reagents JQ1-TCO, JQ1-PA, IBET762-TCO, and IBET151 and plasmids for BRD4 are available from the corresponding authors under a material transfer agreement with Institut Curie, GlaxoSmithKline, and Peter MacCallum Cancer Centre. GlaxoSmithKline holds patent WO 2011054846 A1, which covers IBET151. The ChIP-seq, click-seq, and RNA-seq data are available from the National Center for Biotechnology Information Gene Expression Omnibus repository under accession number GSE88751.