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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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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 [RNA-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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Project description:Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR/Cas9-based gene-editing studies. We observed that myeloma cell resistance to "degraders" of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; involves loss-of-function for the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for CRBN- vs. VHL-based degraders explains mechanistically the lack of cross-resistance for degraders targeting the same protein via different E3 ligase/CRLs.

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