67 research outputs found
The Selectivity of Austocystin D Arises from Cell-Line-Specific Drug Activation by Cytochrome P450 Enzymes
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Mediator Kinase Inhibition Further Activates Super-Enhancer Associated Genes in AML
Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors (TFs), and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling TFs and oncogenes 1, 2. BRD4 and CDK7 are positive regulators of SE-mediated transcription3,4,5. In contrast, negative regulators of SE-associated genes have not been well described. Here we report that Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We determined that the natural product cortistatin A (CA) selectively inhibited Mediator kinases, had antileukaemic activity in vitro and in vivo, and disproportionately induced upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the TFs CEBPA, IRF8, IRF1 and ETV6 6, 7, 8. The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has antileukaemic activity. Individually increasing or decreasing expression of these TFs suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types and can be pharmacologically targeted as a therapeutic approach to AML
Functional Group Compatibility. Propargyl Alcohol Reduction in the Presence of a Vinyl Iodide
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 2: Synthesis of Fragments C 1
Stereoselective synthesis of (E)-α-aryltellurenylvinylstannanes and their application in the synthesis of stereodefined trisubstituted alkenes
An efficient cis-reduction of alkyne to alkene in the presence of a vinyl iodide: stereoselective synthesis of the C22–C31 fragment of leiodolide A
Effect of psychotropic drugs on synaptosomal uptake of H3-?-aminobutyric acid and on Na,K-ATPase activity
Novel Stereoselective Synthesis of (E)-β-Silylvinylstannanes via Hydromagnesiation of Silylarylacetylenes
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