CDK9 inhibitor induces the apoptosis of acute lymphocytic leukemia by inhibiting c-Myc-mediated glycolytic metabolism
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ABSTRACT:
PROVIDER: PRJNA700568 | ENA |
REPOSITORIES: ENA
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Project description:Purpose:the inhibitory effect of CDK9i on the energy metabolism of B-ALL cells remains unclear. To address this question, we collected SNS-032- and DMSO-treated cells for RNA sequencing Methods:REH cells were seeded at a density of 1× 106 cells/ml and treated with 200nm SNS_032 or DMSO for 24h. Results:CDK9i perturbs the glycolytic metabolism of B-ALL cells in vitro.
2021-02-09 | GSE166339 | GEO
Project description: Not available
| S-EPMC7969802 | biostudies-literature
Project description:Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors (ibrutinib or acalabrutinib) and BCL2 antagonists (venetoclax). When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by releasing RNA Polymerase II (POLII) from proximal-promoter pause by way of phosphorylation. The transcripts regulated by P-TEFb are frequently dysregulated in solid tumors and hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. This is due to lack of selective inhibitors and undesirable side-effect profiles of less selective inhibitors. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death as measured by apoptosis in CLL cell lines and primary patient samples. Transcriptome analysis revealed compensatory upregulation in translation machinery and inhibition of RNA degradation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs CDK9 binding partners such as HEXIM1, MEPCE, and LARP7. Finally, C57BL/6J immune competent mice were engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with either VIP152 or vehicle. VIP152-treated mice had a reduction of blood disease over time and an improved overall survival. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.
2023-03-20 | GSE199037 | GEO
Project description:NAA enhances cell yields by inhibiting apoptosis pathway
| PRJNA1027747 | ENA
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
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
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.
2015-06-17 | GSE60952 | GEO
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.
2015-06-17 | GSE60953 | GEO
Project description:CDK9, in complex with cyclin T1 or T2, is essential for mRNA transcription by enabling paused RNA polymerase II to proceed into elongation. Increasing evidence highlights CDK9’s involvement in transcriptional addiction in cancer. In this study, we explored the efficacy of novel CDK inhibitors and demonstrated that targeting CDK9 significantly impairs proliferation and induces apoptosis in various triple-negative breast cancer (TNBC) cell lines. Transcriptomic analysis revealed that CDK9 inhibition caused downregulation of genes governing transcription, cell cycle progression, and oncogenic signalling pathways, such as TGF-β and Wnt/β-catenin signalling. This disruption of transcriptional programs was further enhanced by combining CDK9 and EGFR inhibitors.
2025-09-30 | GSE283178 | GEO
Project description:To understand better the contribution of CDK9 in P. gingivalis-stimulated gene expression, gene chips were performed. Lentiviral vectors carrying CDK9 shRNA or not were transfected into cells for 96 hours, with the assist of Envirus. NC group was transfected with non-targeting scramble and stimulated with PBS. NC and Pg group was transfected with non-targeting scramble and stimulated with P. gingivalis. CDK9 shRNA group was transfected with CDK9 shRNA and stimulated with PBS. CDK9 shRNA and Pg group was transfected with CDK9 shRNA and stimulated with P. gingivalis.
2019-10-11 | GSE138679 | GEO