AT7519, a Cyclin-Dependent Kinase Inhibitor, Exerts Its Effects by Transcriptional Inhibition in Leukemia Cell Lines and Patient Samples

Squires, Matthew; Cooke, Laurence; Lock, Victoria; Qi, Wenqing; Lewis, Edward J.; Thompson, Neil T.; Lyons, John F.; Mahadevan, Daruka

doi:10.1158/1535-7163.mct-09-1071

Cited by 48 publications

(35 citation statements)

References 19 publications

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“…MYCN down-regulation was also induced by CDK inhibitors other than CR8 and roscovitine (Figure 6): MR4 (unpublished), N-&-N1 (23, 24), purvalanol A (57), SCH727965 (58), AT7519 (59), SNS-032 (60) and flavopiridol (61), but not by N6-methyl-CR8 and N6-methylroscovitine (the kinase inactive derivatives of CR8 and roscovitine, respectively) (35). Besides CDKs, roscovitine and CR8 interact with a few other kinases as shown above and earlier (20, 34, 35).…”

Section: Resultsmentioning

confidence: 99%

CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells

et al. 2013

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To understand the mechanisms of action of (R)-roscovitine and (S)-CR8, two related pharmacological inhibitors of cyclin-dependent kinases (CDKs), we applied a variety of ‘-omics’ techniques to the human neuroblastoma SH-SY5Y and IMR32 cell lines: [1] kinase interaction assays, [2] affinity competition on immobilized broad-spectrum kinase inhibitors, [3] affinity chromatography on immobilized (R)-roscovitine and (S)-CR8, [4] whole genome transcriptomics analysis and specific quantitative PCR studies, [5] global quantitative proteomics approach and Western blot analysis of selected proteins. Altogether the results show that the major direct targets of these two molecules belong to the CDKs (1, 2, 5, 7, 9, 12), DYRKs, CLKs, CK1s families. By inhibiting CDK7, CDK9 and CDK12, these inhibitors transiently reduce RNA polymerase 2 activity, which results in down-regulation of a large set of genes. Global transcriptomics and proteomics analysis converge to a central role of MYC transcription factors down-regulation. Indeed CDK inhibitors trigger rapid and massive down-regulation of MYCN expression in MYCN amplified neuroblastoma cells as well as in nude mice xenografted IMR32 cells. Inhibition of casein kinase 1 may also contribute to the antitumoral activity of (R)-roscovitine and (S)-CR8. This dual mechanism of action may be crucial in the use of these kinase inhibitors for the treatment of MYC-dependent cancers, in particular neuroblastoma where MYCN amplification is a strong predictor factor for high-risk disease.

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Section: Resultsmentioning

confidence: 99%

CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells

et al. 2013

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“…Other broad CDK inhibitors include P276-00, a second generation synthetic flavone, SCH 727965 (dinaciclib), and AT7519. These compounds also primarily appear to exert their antitumor effects through additional mechanisms beyond cell cycle inhibition 49–51 .…”

Section: Targeting the Cell Cyclementioning

confidence: 99%

New molecular targets in mantle cell lymphoma

Parekh

Weniger

Wiestner

2011

Seminars in Cancer Biology

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Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by aberrant expression of cyclin D1 due to the translocation t(11;14). Epigenomic and genomic lesions in pathways regulating B-cell activation, cell cycle progression, protein homeostasis, DNA damage response, cell proliferation and apoptosis contribute to its pathogenesis. While patients typically respond to first-line chemotherapy, relapse is the rule resulting in a median survival of 5–7 years. The PI3K/AKT/mTOR appears as a key pathway in the pathogenesis and can be targeted with small molecules. Most experience is with mTOR inhibitors of the rapamycin class. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 are novel options to more effectively target this pathway. Bruton’s tyrosine kinase inhibition by PCI-32765 has promising activity and indicates immunoreceptor signaling as a novel therapeutic target. Up to 50% of relapsed patients respond to the proteasome inhibitor bortezomib suggesting that MCL may be particularly sensitive to disruption of protein homeostasis and/or induction of oxidative stress. Recent work has focused on elucidating the mechanism of bortezomib-induced cytotoxicity and the development of second-generation proteasome inhibitors. DNA hypomethylating agents and histone deacetylase inhibitors effect epigenetic de-repression of aberrantly silenced genes. These epigenetic pharmaceuticals and HSP90 inhibitors can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients a chance to benefit from these advances and is essential to maintain the momentum of progress. Innovative trial designs may be needed to expedite the clinical development of these targeted agents.

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“…All these compounds inhibit CDK9 and appear to primarily exert their antitumor effects through inhibition of transcription. 13-15 With demonstrated activity in preclinical models they have entered clinical testing (Table 1). …”

Section: Targeting the Cell Cyclementioning

confidence: 99%

Molecular Targeted Approaches in Mantle Cell Lymphoma

Weniger

Wiestner

2011

Seminars in Hematology

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Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by the translocation t(11;14) that leads to aberrant expression of cyclin D1. Response to first-line chemotherapy is good but most patients relapse resulting in a median survival of 5-7 years. The important PI3K/AKT/mTOR pathway can be targeted with small molecules. mTOR inhibitors have clinical activity and temsirolimus has been approved in Europe. Second generation mTOR inhibitors and the PI3K inhibitor CAL-101 offer additional means to target the pathway. Promising results with the BTK inhibitor PCI-32765 suggest that B-cell receptor signaling could play a role. For unknown reasons, MCL appears to be particularly sensitive to disruption of protein homeostasis. The proteasome inhibitor bortezomib achieves responses in up to 50% of relapsed patients. Much work has been done in elucidating the mechanism of its cytotoxicity, its incorporation into combination therapies, and the development of second generation proteasome inhibitors. Deacetylase and HSP90 inhibitors are also promising classes of drugs that can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients an immediate chance to benefit from these advances and is essential to maintain the momentum of progress.

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AT7519, a Cyclin-Dependent Kinase Inhibitor, Exerts Its Effects by Transcriptional Inhibition in Leukemia Cell Lines and Patient Samples

Cited by 48 publications

References 19 publications

CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells

CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells

New molecular targets in mantle cell lymphoma

Molecular Targeted Approaches in Mantle Cell Lymphoma

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