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Click chemistry enables comprehensive preclinical evaluation of targeted epigenetic therapies

ABSTRACT: Click chemistry enables comprehensive preclinical evaluation of targeted epigenetic therapies

PROVIDER: PRJNA348447 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR4423330.fastq.gz	Fastqsanger.gz
	SRR4423360.fastq.gz	Fastqsanger.gz
	SRR4423370.fastq.gz	Fastqsanger.gz
	SRR4423331.fastq.gz	Fastqsanger.gz
	SRR4423361.fastq.gz	Fastqsanger.gz

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Click chemistry enables comprehensive preclinical evaluation of targeted epigenetic therapies [Click-Seq 2]

Project description:The success of targeted therapies hinges on our ability to understand the molecular and cellular mechanism of action of these agents. Here we modify various BET bromodomain inhibitors, an exemplar novel targeted therapy, to create functionally conserved compounds that are amenable to click-chemistry and can be used as molecular probes in vitro and in vivo. Using click-proteomics and click-sequencing we provide new mechanistic insights to explain the gene regulatory function of BRD4 and the transcriptional changes invoked by BET inhibitors. In mouse models of acute leukaemia, we use high resolution microscopy and flow cytometry to highlight the underappreciated heterogeneity of drug activity within tumour cells located in different tissue compartments. We also demonstrate the differential distribution and effects of the drug in normal and malignant cells in vivo. These data provide critical insights that reveal the cellular and molecular details for the efficacy and limitations of these agents. This study provides a framework for the pre-clinical assessment of other conventional and targeted therapies.

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Click chemistry enables comprehensive preclinical evaluation of targeted epigenetic therapies

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Project description: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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