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Targeting Transcriptional Addiction by a Novel Highly Selective CDK9 Kinase Inhibitor for AML.

ABSTRACT: Targeting Transcriptional Addiction by a Novel Highly Selective CDK9 Kinase Inhibitor for AML.

PROVIDER: PRJNA508101 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8274684_1.fastq.gz	Fastqsanger.gz
	SRR8274684_2.fastq.gz	Fastqsanger.gz
	SRR8274685_1.fastq.gz	Fastqsanger.gz
	SRR8274685_2.fastq.gz	Fastqsanger.gz
	SRR8274686_1.fastq.gz	Fastqsanger.gz

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Targeting Transcriptional Addiction by a Novel Highly Selective CDK9 Kinase Inhibitor for AML.

Project description:Targeting Transcriptional Addiction by a Novel Highly Selective CDK9 Kinase Inhibitor for AML.

| PRJNA508101 | ENA

Targeting Transcriptional Addiction by a Novel Highly Selective CDK9 Kinase Inhibitor for AML.

Project description:we reported a novel CDK9 high selective inhibitor JSH-009, it displayed high potency against CDK9 (IC50=1nM) and achieved high selectivity over CDKs family kinases (range from 200-10000 fold). JSH-009 showed high potent anti-proliferation effect in a range of AML cells and primary patient cells through downregulation of a number of transcriptional, apoptotic genes and related signaling pathways. In addition, this compound exhibited great anti-leukemic efficacy in the MV4-11 mediated xenograft, engraftment and AML PDX preclinical models. Currently, JSH-009 is under extensive preclinical development and We believe the work presented here would be of great interest to readers of Leukemia.

2019-02-28 | GSE123287 | 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

AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells

Project description:Phosphorylation of RNA polymerase II by cyclin-dependent kinase 9 (CDK9) is crucial for transcriptional regulation, and acute inhibition of CDK9 results in the rapid downregulation of genes with short-lived transcripts and labile proteins. Multiple non-selective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573. Using integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacological comparisons, Mcl-1 depletion was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. AZD4573 suppresses Mcl-1 in a dose- and time-dependent manner that causes caspase-3 cleavage in sensitive cancer cells, most notably in hematological malignancies. This pharmacodynamic response is observed in vivo as well, which leads to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses as monotherapy or in combination with venetoclax. Fully understanding the mechanism, exposure, and anti-tumor activity of AZD4573 also informed the development of a robust PK/PD/efficacy model that helped select and predict the starting and efficacious dose range in man. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematological malignancies (clinicaltrials.gov identifier: NCT03263637).

2020-05-26 | PXD013796 | Pride

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

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

RNA-seq data corresponding to: AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells

Project description:A time-course RNA-seq experiment testing the effect of drug treatment using selective CDK9 inhibitor AZD4573. The experiment was done using a resistant cell-line to AZD4573: the MCF7 breast cancer cell-line.

2019-11-08 | GSE129012 | GEO

Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism: Pol II occupancy profiling by ChIP-Seq in HeLa cell line in the presence or absence of CDK9 inhibition

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. ChIP-seq of Pol II in HeLa cells before or after i-CDk9 treatment

2015-06-17 | E-GEOD-60953 | biostudies-arrayexpress

Selective inhibition of CDK9 in triple negative breast cancer

Project description:Selective inhibition of CDK9 in triple negative breast cancer

| PRJNA764171 | ENA