| Literature DB >> 28619718 |
Dean S Tyler1,2, Johanna Vappiani3, Tatiana Cañeque4,5,6, Enid Y N Lam1,2, Aoife Ward3, Omer Gilan1,2, Yih-Chih Chan1, Antje Hienzsch4,5,6, Anna Rutkowska3, Thilo Werner3, Anne J Wagner3, Dave Lugo7, Richard Gregory7, Cesar Ramirez Molina7, Neil Garton7, Christopher R Wellaway7, Susan Jackson1, Laura MacPherson1,2, Margarida Figueiredo1, Sabine Stolzenburg1, Charles C Bell1,2, Colin House1, Sarah-Jane Dawson1,2,8, Edwin D Hawkins9, Gerard Drewes3, Rab K Prinjha7, Raphaël Rodriguez4,5,6, Paola Grandi10, Mark A Dawson11,2,8,12.
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.Entities:
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Year: 2017 PMID： 28619718 PMCID： PMC5865750 DOI： 10.1126/science.aal2066
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728