Cyclin-dependent kinase 7 is a therapeutic target in high-grade glioma

Greenall, Sameer A.; Lim, Yi Chieh; Mitchell, Camilla B.; Ensbey, Kathleen S.; Stringer, Brett W.; Wilding, Alexander L.; O’Neill, Geraldine M.; McDonald, Kerrie L.; Gough, Daniel J.; Day, Bryan W.; Johns, Terrance G.

doi:10.1038/oncsis.2017.33

Cited by 52 publications

(53 citation statements)

References 39 publications

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“…In this study, we describe a potent and selective CDK7 inhibitor occupancy. These, and published data in nonclinical models of a variety of tumor types, support the hypothesis that tumor cells have a dependency on CDK7 that is distinct from normal cells, providing a rationale for investigating CDK7 inhibitors in the clinic (12)(13)(14)(15)(17)(18)(19)(20)(21)(22)(23). SY-1365 was the first selective CDK7 inhibitor to enter clinical development and is currently being investigated as a single agent and in combination with standardof-care agents in specific groups of pateints with ovarian and breast cancer (NCT03134638).…”

Section: Discussionmentioning

confidence: 71%

“…SY-1365 was the first selective CDK7 inhibitor to enter clinical development and is currently being investigated as a single agent and in combination with standardof-care agents in specific groups of pateints with ovarian and breast cancer (NCT03134638). Development of SY-1365 was motivated by the discovery and characterization of a tool compound, THZ1, which provided validation that covalent CDK7 inhibition through a cysteine residue at position 312 was a viable approach for inhibiting the growth of multiple tumor types in nonclinical models (12)(13)(14)(15)(16)(18)(19)(20)(21)(22)(23). Starting with the THZ1 scaffold, optimization of the three-dimensional shape and electron-withdrawing characteristics of the two rings linking the hinge-binding element to the covalent warhead improved the binding potency (K I ) and the deactivation rate constant (k inact ).…”

Section: Discussionmentioning

confidence: 99%

“…Although the downstream events of CDK7 inhibition have not been fully elucidated, decreased expression of oncogenes, including aberrantly expressed transcription factors associated with superenhancers (SE), has been described (12). Treatment with the small-molecule CDK7 inhibitor THZ1 resulted in apoptosis and inhibition of tumor growth in several human tumor murine xenograft models, including T-cell acute lymphoblastic leukemia (13), high-grade glioma (14), melanoma (15), neuroblastoma (12), medullary thyroid carcinoma (16), hepatocellular carcinoma (17,18), esophageal squamous cell carcinoma (19), nasopharyngeal carcinoma (20), small-cell lung cancer (SCLC; ref. 21), triple-negative breast cancer (TNBC; ref.…”

Section: Introductionmentioning

confidence: 99%

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Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7

Hu¹,

Marineau²,

Rajagopal³

et al. 2019

Cancer Research

106

118

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Recent studies suggest that targeting transcriptional machinery can lead to potent and selective anticancer effects in cancers dependent on high and constant expression of certain transcription factors for growth and survival. Cyclin-dependent kinase 7 (CDK7) is the catalytic subunit of the CDK-activating kinase complex. Its function is required for both cell-cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive cancer target because its inhibition leads to decreased transcript levels of oncogenic transcription factors, especially those associated with super-enhancers. Here, we describe a selective CDK7 inhibitor SY-1365, which is currently in clinical trials in populations of patients with ovarian and breast cancer (NCT03134638). In vitro, SY-1365 inhibited cell growth of many different cancer types at nanomolar concentrations. SY-1365 treatment decreased MCL1 protein levels, and cancer cells with low BCL2L1 (BCL-XL) expression were found to be more sensitive to SY-1365. Transcriptional changes in acute myeloid leukemia (AML) cell lines were distinct from those following treatment with other transcriptional inhibitors. SY-1365 demonstrated substantial antitumor effects in multiple AML xenograft models as a single agent; SY-1365-induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax. Antitumor activity was also observed in xenograft models of ovarian cancer, suggesting the potential for exploring SY-1365 in the clinic in both hematologic and solid tumors. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers. Significance: These findings demonstrate the molecular mechanism of action and potent antitumor activity of SY-1365, the first selective CDK7 inhibitor to enter clinical investigation.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7

Hu¹,

Marineau²,

Rajagopal³

et al. 2019

Cancer Research

106

118

View full text Add to dashboard Cite

show abstract

“…CDK7 has become a potential therapeutic target, and CDK7 inhibitors have entered the clinical trial as promising methods for a variety of malignancies. THZ1 is a covalent inhibitor of CDK7, which shows strong antitumor effects in various cancers by inhibition of CDK7 [9][10][11][12][13][14][15][16] . However, the role of CDK7 and the effect of THZ1 treatment in CCA have not been reported.…”

Section: Introductionmentioning

confidence: 99%

CDK7 inhibitor THZ1 inhibits MCL1 synthesis and drives cholangiocarcinoma apoptosis in combination with BCL2/BCL-XL inhibitor ABT-263

Huang

Ding

et al. 2019

Cell Death Dis

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Cholangiocarcinoma (CCA) is a fatal disease without effective targeted therapy. We screened a small-molecule library of 116 inhibitors targeting different targets of the cell cycle and discovered several kinases, including Cyclin-dependent kinase 7 (CDK7) as vulnerabilities in CCA. Analysis of multiple CCA data sets demonstrated that CDK7 was overexpressed in CCA tissues. Further studies demonstrated that CDK7 inhibitor THZ1 inhibited cell viability and induced apoptosis in CCA cells. We also showed that THZ1 inhibited CCA cell growth in a xenograft model. RNA-sequencing followed by Gene ontology analysis showed a striking impact of THZ1 on DNA-templated transcriptional programs. THZ1 downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition. A number of oncogenic transcription factors and survival proteins, like MCL1, FOSL1, and RUNX1, were repressed by THZ1. MCL1, one of the antiapoptotic BCL2 family members, was significantly inhibited upon THZ1 treatment. Accordingly, combining THZ1 with a BCL2/BCL-XL inhibitor ABT-263 synergized in impairing cell growth and driving apoptosis. Our results demonstrate CDK7 as a potential target in treating CCA. Combinations of CDK7 inhibition and BCL2/BCL-XL inhibition may offer a novel therapeutic strategy for CCA.

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“…5,6 Kwiatkowski et al 7 reported that THZ1 can form a covalent bond by targeting a unique cysteine residue outside the cyclin-dependent kinase 7 (CDK7) kinase domain, which led to the prolonged and irreversible inactivation of CDK7. 7,[9][10][11][12][13] However, no study has been done to explore the possible effects of THZ1 on HCC yet. 8 Moreover, more and more studies illustrated that THZ1 exhibited encouraging therapeutic effects in different tumor types, such as small cell lung cancer, T-ALL, triple-negative breast cancer, ovarian cancer, and high-grade glioma.…”

mentioning

confidence: 99%

Inhibition of cyclin‐dependent kinase 7 suppresses human hepatocellular carcinoma by inducing apoptosis

Zhong

Yang

Jia

et al. 2018

J of Cellular Biochemistry

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Increasing evidence has shown that THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, exhibits therapeutic effects in various tumors. However, the possible effect of THZ1 on hepatocellular carcinoma (HCC) remains unknown. Our study was to investigate the roles of THZ1 in HCC cells and in subcutaneous HCC model and illustrate the molecular mechanisms. The phosphorylation levels of Ser2, Ser5, and Ser7 within RNA polymerase II (RNAPII) C-terminal domain (CTD) and the expression levels of Ki67, Mcl-1, survivin, XIAP, and p53 in HCC cells under different conditions were examined by Western blot analysis. Cell growth and apoptosis were assessed via 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis, respectively. Tumor volume was assessed in HCC mice with THZ1 or vehicle treatment and immunohistochemical (IHC) analysis was conducted on excised tumors. THZ1 significantly inhibited the phosphorylation of Ser2, Ser5, and Ser7 within RNAPII-CTD in the dose-dependent and irreversible manner. MTT assay and flow cytometry analysis showed that THZ1 inhibited HCC cell proliferation and induced apoptosis, respectively. Western blot analysis indicated THZ1 significantly upregulated p53 expression and downregulated the expressions of Mcl-1, survivin, XIAP, and Ki67. THZ1 suppressed tumor growth in Hep3B xenografted mice in a time-dependent manner. IHC analysis indicated that tumors in THZ1 group had less Ki67+ cells and more cleaved caspase-3+ cells than those in vehicle group. THZ1 exhibited anti-HCC effects through irreversibly inhibiting CDK7 activity, decreasing RNAPII-CTD phosphorylation, inducing p53 expression and inhibiting antiapoptotic gene expressions, which subsequently induced apoptosis and inhibited proliferation of HCC cells.

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Cyclin-dependent kinase 7 is a therapeutic target in high-grade glioma

Cited by 52 publications

References 39 publications

Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7

Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7

CDK7 inhibitor THZ1 inhibits MCL1 synthesis and drives cholangiocarcinoma apoptosis in combination with BCL2/BCL-XL inhibitor ABT-263

Inhibition of cyclin‐dependent kinase 7 suppresses human hepatocellular carcinoma by inducing apoptosis

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