Click chemistry enables preclinical evaluation of targeted epigenetic therapies

• Published in: Science (American Association for the Advancement of Science) Vol. 356; no. 6345; pp. 1397 - 1401
• Main Authors: Tyler, Dean S., Vappiani, Johanna, Cañeque, Tatiana, Lam, Enid Y. N., Ward, Aoife, Gilan, Omer, Chan, Yih-Chih, Hienzsch, Antje, Rutkowska, Anna, Werner, Thilo, Wagner, Anne J., Lugo, Dave, Gregory, Richard, Molina, Cesar Ramirez, Garton, Neil, Wellaway, Christopher R., Jackson, Susan, MacPherson, Laura, Figueiredo, Margarida, Stolzenburg, Sabine, Bell, Charles C., House, Colin, Dawson, Sarah-Jane, Hawkins, Edwin D., Drewes, Gerard, Prinjha, Rab K., Rodriguez, Raphaël, Grandi, Paola, Dawson, Mark A.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 30.06.2017; The American Association for the Advancement of Science; American Association for the Advancement of Science (AAAS)
• Subjects: Animal models; Animals; Benzodiazepines - pharmacology; Benzodiazepines - therapeutic use; Bone marrow; Cancer; Cells, Cultured; Chemical Sciences; Chemical synthesis; Chemistry; Chromatin; Click Chemistry; Compartments; Cytometry; Differential distribution; Disease Models, Animal; Drug Delivery Systems; Drugs; Epigenetics; Epigenomics; Flow cytometry; Gene expression; Gene sequencing; Genes; Heterogeneity; In vivo methods and tests; Inhibitors; Leukemia; Leukemia - drug therapy; Leukemia - pathology; Leukemias; Life Sciences; Localization; Mice; Narcotics; Organic Chemistry; Position (location); Precision Medicine; Probes; Proteomics; Spleen; Synthesis (chemistry); Therapy; Tissue Distribution; Transcription; Transcription Factors - antagonists & inhibitors; Tumor cells
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aal2066

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.