Evaluation of CDK9 Inhibition by Dinaciclib in Combination with Apoptosis Modulating izTRAIL for the Treatment of Colorectal Cancer

Shen, Xiao; Kretz, Anna-Laura; Schneider, Sandra; Knippschild, Uwe; Henne‐Bruns, Doris; Kornmann, Marko; Lemke, Johannes; Traub, Benno

doi:10.3390/biomedicines11030928

Cited by 5 publications

(2 citation statements)

References 38 publications

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“…In previous reports, several CDK9 inhibitors had been proven to possess the potential to treat CRC. − However, the correlation between CDK9 and CRC is rarely elucidated. Thus, we first assessed the correlation between CDK9 and CRC based on the GDC-TCGA database (TCGA Colon Adenocarcinoma data set).…”

Section: Resultsmentioning

confidence: 99%

Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation

Zhong,

Xu,

Zhou

et al. 2024

J. Med. Chem.

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Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily. In this work, we preliminarily demonstrated the feasibility of CDK9 as a potent target of treatment for colorectal cancer, and a series of novel CDK9 inhibitors were rationally designed and synthesized based on the structure of AZD5438 (a pan CDKs inhibitor reported by AstraZeneca). A novel selective CDK9 inhibitor named CLZX-205, which possessed significant CDK9 inhibitory activity (IC 50 = 2.9 nM) with acceptable pharmacokinetic properties and antitumor efficacy in vitro and in vivo, was developed. Research on the mechanism indicated that CLZX-205 could induce apoptosis in the HCT116 cell line by inhibiting phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related genes and proteins expression, and these results were validated at the cellular and tumor tissue levels. Currently, CLZX-205 is undergoing further research as a promising candidate for CRC treatment.

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Section: Resultsmentioning

confidence: 99%

Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation

Zhong,

Xu,

Zhou

et al. 2024

J. Med. Chem.

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“…Dinaciclib has been studied in combination with other therapeutics such as heat-shock protein inhibitors [24] and TNF-related apoptosis-inducing ligand (TRAIL) [29] to enhance its anticancer effects. Its broader target profile with four different inhibited CDKs makes it more amenable to combination approaches, allowing synergistic effects in cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Impact of CDK Inhibitors on TBXT Expression in Chordoma Cell Lines Including the First Stable Cell Line of a High-Grade Chordoma

Bette,

Haase,

Nell

et al. 2024

Diagnostics

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Chordomas are very rare malignant neoplasms of the bone occurring almost exclusively along the spine. As the tumours are thought to arise from notochordal remnants, the vast majority of chordomas express the TBXT gene, resulting in detectable nuclear amounts of its gene product brachyury. This T-Box transcription factor is commonly recognised as being essential in chordoma cells, and limiting TBXT expression is thought to be the key factor in controlling this tumour. Although the tumour is rare, distinct molecular differences and vulnerabilities have been described with regard to its location and the progression status of the disease, rendering it mandatory for novel cell lines to reflect all relevant chordoma subtypes. Here, we describe a novel chordoma cell line arising from the pleural effusion of a disseminated, poorly differentiated chordoma. This cell line, U-CH22, represents a highly aggressive terminal chordoma and, therefore, fills a relevant gap within the panel of available cell culture models for this orphan disease. CDK7 and CDK9 inhibition was lately identified as being effective in reducing viability in four chordoma cell lines, most likely due to a reduction in brachyury levels. In this study, we determined the capability of the CDK7 inhibitor THZ1 and the CDK1/2/5/9 inhibitor dinaciclib to reduce TBXT expression at mRNA and protein levels in a broad range of nine cell lines that are models of primary, recurrent, and metastasised chordoma of the clivus and the sacrum.

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Transcriptional regulation and therapeutic potential of cyclin-dependent kinase 9 (CDK9) in sarcoma

Walker,

Hornicek,

Duan

2024

Biochemical Pharmacology

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Evaluation of CDK9 Inhibition by Dinaciclib in Combination with Apoptosis Modulating izTRAIL for the Treatment of Colorectal Cancer

Cited by 5 publications

References 38 publications

Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation

Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation

Impact of CDK Inhibitors on TBXT Expression in Chordoma Cell Lines Including the First Stable Cell Line of a High-Grade Chordoma

Transcriptional regulation and therapeutic potential of cyclin-dependent kinase 9 (CDK9) in sarcoma

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