RNA-seq data corresponding to: AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE129012 | GEO | 2019/11/08
REPOSITORIES: GEO
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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
Project description:RNA-seq data corresponding to: AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells
| PRJNA529703 | ENA
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 pancreatic cancer cell line HPAF-II carrying KRAS G12D mutation.
2024-08-31 | GSE270409 | 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. 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:Analog-sensitive kinase technology allows for specific inhibition of a given kinase. Here we utilize an analog-sensitive CDK9 cell line to determine the impact of CDK9 inhibition on the phospho-proteome of human cells. Specifically, we aim to identify substrates of CDK9 in a quantitative way using stable isotope labeling by amino acids in cell culture (SILAC) followed by LC-MS/MS.
2019-11-11 | PXD014825 | Pride
Project description:CDK9 is a critical kinase required for the productive transcription of protein-coding genes by RNA polymerase II (pol II) in higher eukaryotes. Phosphorylation of targets including the elongation factor SPT5 and the carboxyl-terminal domain (CTD) of RNA pol II allow the polymerase to pass an early elongation checkpoint (EEC), which is encountered soon after initiation. In addition to halting RNA polymerase II at the EEC, CDK9 inhibition also causes premature termination of transcription across the last exon, loss of polyadenylation factors from chromatin, and loss of polyadenylation of nascent transcripts. Inhibition of the phosphatase PP2A abrogates the premature termination and loss of polyadenylation caused by CDK9 inhibition, suggesting that CDK9 and PP2A, working together, regulate the coupling of elongation and transcription termination to RNA maturation. Our phosphoproteomic analyses, using either DRB or an analog-sensitive CDK9 cell line confirm the splicing factor SF3B1 as an additional key target of this kinase. CDK9 inhibition causes loss of interaction of splicing and export factors with SF3B1, suggesting that CDK9 also helps to co-ordinates coupling of splicing and export to transcription.
2022-08-22 | PXD026720 | Pride
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: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
Project description:Targeted treatment for triple-negative breast cancer (TNBC) remains an elusive clinical challenge. Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator shown to promote growth of multiple cancers, including TNBC, and represents a potential new therapeutic target. CDK9 increases RNA Polymerase II (Pol II) activity, which facilitates sustained expression of short-lived oncogenic and anti-apoptotic proteins. However, pre-clinical evaluation of CDK9 as a therapeutic target has been hampered by the poor selectivity of existing CDK9 inhibitors (CDK9i). Here, we report a novel CDK9i; D11-8, which exhibits high potency against CDK9 (Ki = 8 nM) and displays remarkable selectivity over other CDKs and human kinases. D11-8 inhibited TNBC cell line proliferation,, induced G2/M cell cycle arrest, and increased apoptosis. Mechanistically, D11-8 inhibited CDK9; reducing Pol II phosphorylation, down-regulating expression of proto-oncogene MYC and anti-apoptotic marker MCL1, and dramatically inducing Pol II promoter-proximal pausing at MYC, G2/M checkpoint, and E2F2 target genes. D11-8 was further validated for TNBC in vivo, and inhibited TNBC cell line tumour growth without toxicity. To further elucidate the cancer cell specificity of D11-8, normal breast tissue was collected from women undergoing reduction mammoplasty surgery and treated with D11-8 ex vivo as patient-derived explants. High doses of D11-8 (2.7 µM) had no effect on the proliferative capacity of normal breast epithelial cells (Ki67 positivity), and tissues appeared histologically normal. Collectively, these data demonstrate that D11-8 effectively inhibits CDK9 in TNBC cell lines, resulting in growth inhibition without short-term toxicity.
2023-11-25 | GSE184335 | GEO
Project description:Mcl-1, a pro-survival member of the Bcl-2 protein family, is an attractive target for cancer therapy. We have recently identified the natural product marinopyrrole A (maritoclax) as a novel small molecule Mcl-1 inhibitor. Here, we describe the structure-activity relationship study of pyoluteorin derivatives based on maritoclax. To date, we synthesized over 30 derivatives of maritoclax and evaluated their inhibitory actions and cytotoxicity toward Mcl-1-dependent cell lines. As a result, several functional groups were identified in the pyoluteorin motif that significantly potentiate biological activity. A number of such derivatives, KS04 and KS18, interacted with Mcl-1 in a conserved fashion according to NMR spectroscopy and molecular modeling. KS04 and KS18 induced apoptosis selectively in Mcl-1-dependent but not Bcl-2-dependent K562 cells through selective Mcl-1 down-regulation, and synergistically enhanced apoptosis in combination with ABT-737. Moreover, the intraperitoneal administration of KS18 (10 mg/kg/d) and ABT-737 (20 mg/kg/d) significantly suppressed the growth of ABT-737-resistant HL-60 xenografts in nude mice without apparent toxicity. Overall, we identified the pharmacophore of pyoluteorin derivatives that act as potent and promising Mcl-1 antagonists against Mcl-1-dependent hematological cancers.
| S-EPMC4623387 | biostudies-literature