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Rational design and development of selective BRD7 bromodomain inhibitors and their activity in prostate cancer

ABSTRACT: Rational design and development of selective BRD7 bromodomain inhibitors and their activity in prostate cancer

PROVIDER: PRJNA950400 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24030200_1.fastq.gz	Fastqsanger.gz
	SRR24030200_2.fastq.gz	Fastqsanger.gz
	SRR24030201_1.fastq.gz	Fastqsanger.gz
	SRR24030201_2.fastq.gz	Fastqsanger.gz
	SRR24030202_1.fastq.gz	Fastqsanger.gz

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Rational design and development of selective BRD7 bromodomain inhibitors and their activity in prostate cancer

Project description:Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer.1,2 Bromodomain-containing protein 7 (BRD7) has been implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease.3–13 Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a hydrophobic region unique to BRD7. We synthesized a series of ligands designed to occupy this binding region and identified two BRD7-selective inhibitors, 1-78 and 2-77, which show high affinity for the BRD7 BD and selectivity over the BRD9 BD using thermal shift assays and competitive fluorescence polarization. Our binding mode analyses indicate that these ligands occupy the hydrophobic region in BRD7 and maintain key interactions with the Asn and Tyr residues critical for acetyllysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer. We then performed gene expression profiling analysis using data obtained from RNA-seq of LNCaP cells with or without drug treatment.

2023-11-22 | GSE228587 | GEO

Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer.

Project description:Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer. Bromodomain-containing protein 7 (BRD7) is implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease. Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a binding pocket exclusive to BRD7. We synthesized a series of ligands designed to occupy this binding region and identified two inhibitors with increased selectivity toward BRD7, 1-78 and 2-77, which bind with submicromolar affinity to the BRD7 BD. Our binding mode analyses indicate that these ligands occupy a uniquely accessible binding cleft in BRD7 and maintain key interactions with the asparagine and tyrosine residues critical for acetylated lysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer.

| S-EPMC10641717 | biostudies-literature

BRD7 is a candidate tumour suppressor gene required for p53 function

Project description:Oncogene-induced senescence (OIS) is a p53-dependent defence mechanism against uncontrolled proliferation. Consequently, many human tumours harbour p53 mutations while others show a dysfunctional p53 pathway, frequently by unknown mechanisms. We identified BRD7, a bromodomain-containing protein whose inhibition allows full neoplastic transformation in the presence of wild-type p53. Intriguingly, in human breast tumours harbouring wild-type, but not mutant p53, the BRD7 gene locus was frequently deleted and low BRD7 expression was found in a subgroup of tumours. Functionally, BRD7 is required for efficient p53-mediated transcription of a subset of target genes. BRD7 interacts with p53 and p300, and is recruited to target gene promoters, affecting histone acetylation, p53 acetylation, and promoter activity. Thus, BRD7 suppresses tumourigenicity by serving as a p53 cofactor required for efficient induction of p53-dependent OIS. We recorded mRNA expression profiles of BJ primary fibroblasts expressing the oncogene RasV12 and either control vector, one of two BRD7 knockdown vectors, or p53 knockdown vector. In addition, we profiled genome-wide protein DNA interactions for p53 and BRD7 using ChIP-Seq. p53- and BRD7-binding sites were recorded in RasV12-expressing BJ cells; as a control we used knockdown of the gene of interest (BRD7 or p53).

2010-03-14 | E-GEOD-20076 | biostudies-arrayexpress

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Project description:Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

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BRD7 is a candidate tumour suppressor gene required for p53 function

2010-03-14 | GSE20076 | GEO

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Project description:Rational design of cyanobacteria aptamer sensitizes prostate cancer to hormone therapy

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Human BJ fibroblasts containing control vs. BRD7 shRNA

Project description:Transcriptional profiling of human BJ fibroblasts comparing control FF shRNA expressing cells vs. BRD7 shRNA expressing cells under two conditions, either untreated or treated with 8uM nutln-3a for 8 hours. This experiment was done using two independent shRNAs targeting BRD7. Nutlin-3a was used to stabilize p53 and induce its transcriptional activity. Two-condition experiment, FF shRNA cells vs. BRD7 shRNAs cells in two experimental conditions, either untreated or treated with nutlin-3a.

2010-07-01 | E-GEOD-22607 | biostudies-arrayexpress

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Project description:We applied Chromatin immunoprecipation and massively parallel DNA sequencing technique, ChIP-seqencing, to identify the binding sites of Brd7 protein in human cells. ChIP-seq was applied to HEK293 cell line in control and BRD7 overexpressed cells.

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LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor.

Project description:The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in?vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.

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