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Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands

ABSTRACT: Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands

PROVIDER: PRJNA392134 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5762030.fastq.gz	Fastqsanger.gz
	SRR5762040.fastq.gz	Fastqsanger.gz
	SRR5762031.fastq.gz	Fastqsanger.gz
	SRR5762041.fastq.gz	Fastqsanger.gz
	SRR5762032.fastq.gz	Fastqsanger.gz

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Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands [RNA-seq]

Project description:The addressable pocket of a target protein is often not functionally relevant. This is particularly true for multidomain gene regulatory proteins, such as the bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous human cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders.

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Project description:Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands [RNA-Seq 2]

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Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands

Project description:This SuperSeries is composed of the SubSeries listed below.

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Project description:Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands [ChIP-seq]

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Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands.

Project description:The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24. Using dTRIM24 to probe TRIM24 function, we characterize the dynamic genome-wide consequences of TRIM24 loss on chromatin localization and gene control. Further, we identify TRIM24 as a novel dependency in acute leukemia. Pairwise study of TRIM24 degradation versus bromodomain inhibition reveals enhanced anti-proliferative response from degradation. We offer dTRIM24 as a chemical probe of an emerging cancer dependency, and establish a path forward for numerous selective yet ineffectual ligands for proteins of therapeutic interest.

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Genetic vulnerabilitis study in VHL mutant cells

Project description:VHL has been known as a tumour suppressor gene, also is an essential gene for some proteolysis-targeting chimera (PROTAC) degraders. Here by using CRISPR-cas9 genome wide screening we find that VHL mutation results in strong proliferation defect by HIF1A . VHL MUT shows malfunction of mitochondria which can be restored by HIF1A inhibition. VHL MUT bear specific genetic vulnerabilities which are druggable and mainly HIF1A dependent. In OE33 and MCF7, additional HIF1A inhibition on VHL MUT allows a complete ARV-771 drug resistance acquisition. Our study reports the consequence of VHL mutation and HIF1A dependent druggable genetic vulnerabilities in VHL mutant renal epithelial cells and possible PROTAC resistance acquisition mechanism in breast and oesophageal cancers, provides potential therapeutic targets and strategies for early precancerous and established cancerous cells.

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