Click chemistry enables preclinical evaluation of targeted epigenetic therapies

Dean S. Tyler, Johanna Vappiani, Tatiana Cañeque, Enid Y.N. 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 StolzenburgCharles C. Bell, Colin House, Sarah Jane Dawson, Edwin D. Hawkins, Gerard Drewes, Rab K. Prinjha, Raphaël Rodriguez, Paola Grandi, Mark A. Dawson

Research output: Contribution to journalArticleResearchpeer-review

103 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1397-1401
Number of pages5
Issue number6345
Publication statusPublished - 30 Jun 2017
Externally publishedYes

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