Journal
SCIENCE
Volume 356, Issue 6345, Pages 1397-1401Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aal2066
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Funding
- National Health and Medical Research Council of Australia [1106444, 1085015, 1106447]
- Senior Leukaemia Foundation Australia Fellowship
- VESKI Innovation Fellowship
- Leukaemia Foundation Australia
- Victoria Cancer Agency
- European Union [BLUEPRINT/282510]
- Emergence Ville de Paris Program
- European Research Council under the European Union's Horizon 2020 research and innovation program [647973]
- National Health and Medical Research Council of Australia [1085015, 1106444, 1106447] Funding Source: NHMRC
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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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