Gene expression profiling of MDA-MB-231 cells treated Compound 28, a CDK9 degrader
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PROVIDER: PRJNA1189447 | ENA |
REPOSITORIES: ENA
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Project description:Triple-negative breast cancer (TNBC) is highlyaggressive with very limited treatment options due to the lack of efficient targeted therapies and thus still remains clinically challenging. Targeting CDK9 to remodel transcriptional regulation shows great promisein cancer therapy. We synthesized new series of heterobifunctional molecules ashighly selective and efficacious CDK9 degraders, enabling potentinhibition of TNBC cell growth and rapidly targeted degradationof CDK9. Moreover, the CDK9 degrader (compound 28) was used to treat on TNBC cell lines and the gene expression profile was performed by RNA-seq.
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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
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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Project description:Selective CDK9 inhibition by natural compound toyocamycin in cancer cell
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Project description:Development of a selective CDK9 degrader from a multi-targeted CDK inhibitor
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Project description:Aberrant transcription in cancer cells is characterized by silencing of tumor suppressor genes (TSG) and activation of oncogenes. Transcriptomic changes are associated with epigenomic alterations such as DNA hypermethylation, histone deacetylation, and chromatin condensation in promoter regions of silenced TSG. To discover novel drugs that trigger tumor suppressor genes reactivation in cancer cells, we used a GFP reporter system whose expression is silenced by promoter DNA hypermethyation and histone deacetylation. After screening a natural product drug library, we identified toyocamycin, an adenosine analog that induced potent GFP reactivation and loss of clonogenicity in human colon cancer cells. Toyocamycin induced a downregulation in gene pathways involved in RNA pol II transcription regulation. Connectivity mapping analysis revealed that toyocamycin produced a pharmacological signature mimicking cyclin-dependent kinase (CDK) inhibitors. Using RNA-sequencing, we showed that toyocamycin transcriptomic signature closely resembled the profile of a specific CDK9 inhibitor (HH1). Specific inhibition of RNA pol II phosphorylation level and enzymatic kinase assays confirmed that toyocamycin inhibits specifically CDK9 (IC50 = 79nM) with a greater efficacy than other CDKs (IC50 values between 0.67-15µM). Molecular docking showed that toyocamycin binds efficiently CDK9 catalytic site with a different pose than in other CDKs, which was explained by the binding contribution of specific amino acids within the catalytic pocket and the backbone of the protein. Altogether, we demonstrated that toyocamycin exhibits specific CDK9 inhibition in cancer cells, highlighting its potential for cancer chemotherapy.
2022-05-14 | GSE202744 | 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:Aberrant hyperactivation of cyclins results in carcinogenesis and therapy resistance in cancers. Direct degradation of the specific cyclin or CDK-cyclin complex by small-molecule degraders remains a great challenge. Here, we applied the first application of hydrophobic tagging to induce degradation of CDK9-cyclin T1 heterodimer which is required to keep productive transcription of oncogenes in cancers. LL-K9-3 was identified as a potent small-molecule degrader of CDK9-cyclin T1. Quantitative and time-resolved proteome profiling exhibited LL-K9-3 induced selective and synchronous degradation of CDK9 and cyclin T1. The expression of androgen receptor (AR) and c-Myc were reduced by LL-K9-3 in 22RV1 cells. LL-K9-3 exhibited enhanced anti-proliferative and pro-apoptotic effects than its parental CDK9 inhibitor SNS032, and suppressed downstream signaling of CDK9 and AR more effectively than SNS032. Moreover, LL-K9-3 inhibited AR and MYC-driven oncogenic transcriptional programs, and exerted stronger inhibitory effects on several intrinsic target genes of AR than the monomeric CDK9 PROTAC (Thal-SNS032).
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Project description:The HDAC/G4 dual compound a6 was developed to improve G4 targeting efficiency and anticancer activity in triple-negative breast cancer cells. In order to explore the relationship between G4 functions and a6 treatment, we performed RNA-seq to analyze the proportion of G4-related differentially expressed genes and KEGG pathway enrichment.
2022-11-30 | GSE188629 | 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. ChIP-seq of Pol II in HeLa cells before or after i-CDk9 treatment
2015-06-17 | E-GEOD-60953 | biostudies-arrayexpress