Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CDK9 inhibitor induces the apoptosis of acute lymphocytic leukemia by inhibiting c-Myc-mediated glycolytic metabolism

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166339 | GEO | 2021/02/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

2017-09-01 | GSE89385 | GEO

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

2017-09-01 | GSE89384 | GEO

Characterization of co-transcriptional splicing in acute lymphoblastic leukemia

Project description:Alternative splicing is a promising therapeutic target in acute lymphoblastic leukemia. Here, we report the alternative splicing changes in B-ALL cell lines including NALM6 cells and MUTZ-5 cells treated with DYRK1 inhibitor, EHT 1610 and GNF 2133. Dysregulation of co-transcriptional splicing is a therapeutic target in acute lymphoblastic leukemia (ALL). Here, we detected the alternative splicing in NALM6 cells or MUTZ-5 cells treated with EHT 1610 or GNF2133. We detected the alternative splicing in NALM6 cells cells treated with THAL-SNS-032. We also determined the alternative splicing in MEF2D-BCL9 ALL and MEF2D-HNRNPUL1 ALL patient xenografted samples treated with E7820, a anticancer sulfamide, or DMSO. Furthermore, ChIP-seq for RNA polymerase II (Pol II), p-Ser2 Pol II, and p-Ser5 Pol II were performed after DMSO or EHT 1610 treatment in NALM6 cells. ChIP-seq for p-Ser2 Pol II, and p-Ser5 Pol II were performed after DMSO or THAL-SNS-032 treatment in NALM6 cells.PRO-seq in NALM6 cells treated with DMSO, EHT 1610, and THAL-SNS-032 were performed.

2024-09-09 | GSE252550 | GEO

Piperlongumine (PL) conjugates induce targeted protein degradation

Project description:PROteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS-032, a CDK9 inhibitor. To evaluate the specificity of the PL-SNS-032 lead conjugate named 955, TMT-based proteomics were conducted to compare 955 with its warhead SNS-032 in MOLT4 cells. As expected, cells exhibited a significant reduction of CDK9 after treatment with 0.1 µM 955 for 1 h and 6 h while treatment with 1 µM SNS-032 for 6 h had no significant effect on CDK9. Interestingly, 955, but not SNS-032, can also potently degrade CDK10.

2024-05-24 | PXD039385 | Pride

Identification of the E3 ligase(s) recruited by 955 to degrade CDK9

Project description:PROTACs induce the degradation of target proteins by hijacking an E3 ligase. However, it is usually difficult to directly identify the E3 ligase recruited by a new E3 ligase ligand in a PROTAC using the co-immunoprecipitation method because the formation of the complex is transient and very dynamic. TurboID assay is a powerful proximity labeling method that can sensitively detect weak and transient protein-protein interactions by biotinylating proteins that interact with a bait protein fused with an engineered biotin ligase. Here, we adapted TurboID technology to identify and characterize the specific E3 ligase(s) recruited by 955, a potent piperlongumine (PL)-SNS-032 conjugated CDK9 PROTAC, to mediate CDK9 degradation.

2024-05-24 | PXD039401 | Pride

Genome-wide map of Pol II occupancy alterations on chromatin upon CDK12 and CDK13 inhibition (ChIP-Seq)

Project description:We performed ChIP-Seq on MV4;11 cells after 6 hours treatment of DMSO, 100nM and 200nM THZ531 to determine the location of Pol II occupancy

2020-04-29 | GSE141371 | GEO

Genome-wide map of Pol II occupancy alteration on chromatin upon CDK12 and CDK13 inhibition (ChIP-Seq)

Project description:We performed ChIP-Seq on MV4;11 cells after 6 hours treatment of DMSO, 100nM and 200nM THZ531 to determine the location of Pol II with phosphorylated Ser2 occupancy

2020-04-29 | GSE141369 | GEO

Investigating the effect of CDK inhibition in EML4-ALK cells by ChIP-seq for RNA polymerase II.

Project description:RNA polymerase II ChIP-seq in human H3122 CrizR1 cells treated with DMSO, 200nM alvocidib or 100nM THZ1.

2020-05-13 | E-MTAB-8380 | biostudies-arrayexpress

Gene expression changes in REH following CDC42 inhibition

Project description:ARHGEF4 expression is associated with t(12;21) acute lymphoblastic leukaemia (ALL). Our study investigated the substrate specificity of ARHGEF4, a member of the diffuse B-cell lymphoma (DBL) family of guanine nucleotide exchange factors (GEFs), in t(12;21) ALL REH cells. ARHGEF4 was found to activate the small guanine nucleotide binding protein (GTPase) CDC42. In order to determine the function of CDC42 in t(12;21) ALL cells, we performed RNAseq analysis on REH cells treated for 24 hours with DMSO vehicle control in comparison to 25uM ML141, a CDC42 inhibitor.

2020-06-20 | GSE152836 | GEO

Transcriptome profile of OVCAR3 cells treated with DMSO or THZ531 (200nM) for 6hr

Project description:Transcriptome profile of OVCAR3 cells treated with DMSO or THZ531 (200nM) for 6hr

| PRJNA922206 | ENA