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

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

PROVIDER: PRJNA659371 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12516335.fastq.gz	Fastqsanger.gz
	SRR12516336.fastq.gz	Fastqsanger.gz
	SRR12516337.fastq.gz	Fastqsanger.gz
	SRR12516338.fastq.gz	Fastqsanger.gz
	SRR12516339.fastq.gz	Fastqsanger.gz

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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.

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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

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

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

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

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