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Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ChIP-seq]

ABSTRACT: Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ChIP-seq]

PROVIDER: PRJNA659348 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12516321.fastq.gz	Fastqsanger.gz
	SRR12516322.fastq.gz	Fastqsanger.gz
	SRR12516323.fastq.gz	Fastqsanger.gz
	SRR12516324.fastq.gz	Fastqsanger.gz
	SRR12516325.fastq.gz	Fastqsanger.gz

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Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 InhibitorsModulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

Project description:Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 InhibitorsModulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

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Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [SLAM-seq]

Project description:Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [SLAM-seq]

| PRJNA659371 | ENA

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ATAC-seq]

Project description:Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ATAC-seq]

| PRJNA659350 | ENA

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [SLAM-seq]

Project description:Castration resistant prostate cancers (CRPCs) lose sensitivity to androgen deprivation therapies but frequently remain dependent on oncogenic transcription driven by androgen receptor (AR) and its splice variants. To discover novel modulators of AR variant activity, we used a lysate-based small molecule microarray (SMM) assay and identified KI-ARv-03 as an AR variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742 , an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo , oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.

2020-10-05 | GSE156884 | GEO

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ChIP-seq]

2020-10-05 | GSE156882 | GEO

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ATAC-seq]

2020-10-05 | GSE156881 | GEO

Development of a selective CDK9 degrader from a multi-targeted CDK inhibitor [ChIP-seq]

Project description:Cyclin dependent kinase 9 (CDK9), a key regulator of transcriptional elongation, has long been considered a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. However, despite promising early clinical data in blood cancers using pan-CDK inhibitors that potently inhibit CDK9 such as Dinaciclib and Flavopiridol, no selective CDK9 inhibitors have been clinically approved. Here we show that a multi-targeted CDK inhibitor can be used to develop a selective CDK9 degrader exemplified by THAL-SNS-032, a hetero-bifunctional molecule composed of SNS-032, a CDK2,7,9 inhibitor conjugated to thalidomide, a small molecule binder of Cereblon. We demonstrate that THAL-SNS-032 can recruit the E3 ubiquitin ligase Cereblon to CDK9 and induce its proteasome-mediated degradation. Treatment of cells with low nanomolar concentrations of THAL-SNS-032 resulted in rapid and efficient CDK9 degradation but did not affect levels of other SNS-032 targets, including CDK2 and CDK7. Consistent with this selective degradation phenotype, transcriptional profiling of THAL-SNS-032 indicated that its transcriptional effects were more similar to that of a selective CDK9 inhibitor, NVP2, than that of the nonselective SNS-032 parent compound. Moreover, THAL-SNS-032, in contrast to traditional CDK9 inhibitors, retained potent pro-apoptotic activity even after compound removal from cells. This suggests that degradation of CDK9 leads to prolonged cytotoxic effects as compared to CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation may be a promising strategy for converting multi-targeting inhibitors into selective degraders, and that the pharmacological effects of kinase degradation can be distinct from kinase inhibition.

2017-09-01 | GSE89384 | GEO

Development of a selective CDK9 degrader from a multi-targeted CDK inhibitor [RNA-seq]

2017-09-01 | GSE89385 | GEO

Transcription profiling time series of fission yeast after selective inhibition of Mcs6 and Cdk9

Project description:Selective inhibition of S. pombe Mcs6, Cdk9, or both via bulky nucleotide analogue.

2009-03-30 | E-MEXP-1746 | biostudies-arrayexpress

Expression profiling of HeLa cell line treated with CDK9 inhibitor

Project description:CDK9 is the kinase subunit of P-TEFb that enables RNA polymerase (Pol) II to transit from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to the lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9’s activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb’s loss of activity, only the simultaneous inhibition of CDK9 and MYC can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy. We used microarrays to examine the global impact on gene expression by imhibiting CDK9 at different time durations. HeLa cell lines treated with CDK9 inhibitor at different time points

2015-06-17 | E-GEOD-60952 | biostudies-arrayexpress

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