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Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer

ABSTRACT: Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer

PROVIDER: PRJNA743059 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15015530_1.fastq.gz	Fastqsanger.gz
	SRR15015530_2.fastq.gz	Fastqsanger.gz
	SRR15015531_1.fastq.gz	Fastqsanger.gz
	SRR15015531_2.fastq.gz	Fastqsanger.gz
	SRR15015532_1.fastq.gz	Fastqsanger.gz

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Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer.

Project description:PurposeThe bromodomain and extraterminal (BET)-containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off-target effects, toxicity, and rapid resistance.Experimental designWe have developed a series of molecules that target BET bromodomain proteins through their proteasomal degradation, improving efficacy and specificity of standard inhibitors. We tested their efficacy by utilizing prostate cancer cell lines and patient-derived xenografts, as well as several techniques including RNA-sequencing, mass spectroscopic proteomics, and lipidomics.ResultsBET degraders function in vitro and in vivo to suppress prostate cancer growth. These drugs preferentially affect AR-positive prostate cancer cells (22Rv1, LNCaP, VCaP) over AR-negative cells (PC3 and DU145), and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling at lower concentrations than BET inhibitors. We also identified increases in polyunsaturated fatty acids (PUFA) and thioredoxin-interacting protein (TXNIP) as potential pharmacodynamics biomarkers for targeting BET proteins.ConclusionsCompounds inducing the pharmacologic degradation of BET proteins effectively target the major oncogenic drivers of prostate cancer, and ultimately present a potential advance in the treatment of mCRPC. In particular, our compound dBET-3, is most suited for further clinical development.

| S-EPMC6606381 | biostudies-literature

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.

2018-03-05 | GSE100572 | GEO

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

2018-03-05 | GSE100571 | GEO

Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer

Project description:RNA-seq on VCaP, 22Rv1, and DU145 cells treated with BET-inhibitors and BET-Degradaing molecules

2021-07-08 | GSE179282 | GEO

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

2018-03-05 | GSE106579 | GEO

Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands

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

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A gut microbe-focused metabolomics pipeline enables mechanistic interrogation of microbiome metabolism (part-II)

Project description:The C18 positive mode data for A gut microbe-focused metabolomics pipeline enables mechanistic interrogation of microbiome metabolism.

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Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer (microarray)

Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Two-color experiment, in duplicates

2014-04-25 | E-GEOD-55063 | biostudies-arrayexpress

Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer (ChIP-Seq)

2014-04-25 | E-GEOD-55062 | biostudies-arrayexpress

Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins

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.

2021-02-12 | GSE162205 | GEO

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