Novel cyclin-dependent kinase 9 (CDK9) inhibitor with suppression of cancer stemness activity against non-small-cell lung cancer

Wang, Xin; Yu, Chenhua; Wang, Cheng; Ma, Yakun; Wang, Tianqi; Li, Yao; Huang, Zhi; Zhou, Manqian; Sun, Peiqing; Zheng, Jian‐Yu; Yang, Shengyong; Fan, Yan; Xiang, Rong

doi:10.1016/j.ejmech.2019.07.038

Cited by 34 publications

(27 citation statements)

References 54 publications

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“…Inhibiting CDK9 activity also suppressed the expressions of the stemness markers in the two NSCLC cell lines-SOX2, OCT4, NANOG and KIF4, while also significantly inhibiting other stemness phenotypes like Side Population (SP) and serum-free suspension culture. Lastly, 21e also inhibited the tumor growth of a mouse xenograft model derived from the NSCLC cell line H1299, once more validating the significance of CDK9 in lung cancer [ 104 ].…”

Section: The Clinical Relevance Of Cdk9mentioning

confidence: 94%

Targeting CDK9 for Anti-Cancer Therapeutics

Mandal

Becker

Strebhardt

2021

Cancers

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Cyclin Dependent Kinase 9 (CDK9) is one of the most important transcription regulatory members of the CDK family. In conjunction with its main cyclin partner—Cyclin T1, it forms the Positive Transcription Elongation Factor b (P-TEFb) whose primary function in eukaryotic cells is to mediate the positive transcription elongation of nascent mRNA strands, by phosphorylating the S2 residues of the YSPTSPS tandem repeats at the C-terminus domain (CTD) of RNA Polymerase II (RNAP II). To aid in this process, P-TEFb also simultaneously phosphorylates and inactivates a number of negative transcription regulators like 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) Sensitivity-Inducing Factor (DSIF) and Negative Elongation Factor (NELF). Significantly enhanced activity of CDK9 is observed in multiple cancer types, which is universally associated with significantly shortened Overall Survival (OS) of the patients. In these cancer types, CDK9 regulates a plethora of cellular functions including proliferation, survival, cell cycle regulation, DNA damage repair and metastasis. Due to the extremely critical role of CDK9 in cancer cells, inhibiting its functions has been the subject of intense research, resulting the development of multiple, increasingly specific small-molecule inhibitors, some of which are presently in clinical trials. The search for newer generation CDK9 inhibitors with higher specificity and lower potential toxicities and suitable combination therapies continues. In fact, the Phase I clinical trials of the latest, highly specific CDK9 inhibitor BAY1251152, against different solid tumors have shown good anti-tumor and on-target activities and pharmacokinetics, combined with manageable safety profile while the phase I and II clinical trials of another inhibitor AT-7519 have been undertaken or are undergoing. To enhance the effectiveness and target diversity and reduce potential drug-resistance, the future of CDK9 inhibition would likely involve combining CDK9 inhibitors with inhibitors like those against BRD4, SEC, MYC, MCL-1 and HSP90.

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Section: The Clinical Relevance Of Cdk9mentioning

confidence: 94%

Targeting CDK9 for Anti-Cancer Therapeutics

Mandal

Becker

Strebhardt

2021

Cancers

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“…Notably, most clinical transcriptional CDK inhibitors have hit multiple CDKs. CDK9 has been shown to be a promising and druggable target in oncology for attenuating oncogenic transcription for a variety of indications (Blake et al, 2019;Brisard et al, 2018;Franco et al, 2018;Hashiguchi et al, 2019;Mitra et al, 2016;Morales and Giordano, 2016;Wang et al, 2019). However, as CDK9 also plays a global role in transcription, a sufficient therapeutic index for clinical benefit has not yet been demonstrated.…”

Section: Discovery Of Ki-arv-03 As a Modulator Of Ar Transcriptional Outputmentioning

confidence: 99%

Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

Richters

Doyle

Freeman³

et al. 2021

Cell Chemical Biology

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“…Another class of kinases being explored for use in combination with BH3-mimetics are cyclin-dependent kinase inhibitors, specifically those involved in gene transcription such as CDK9. CDK9 regulates transcription of oncogenic genes including MYC and is essential for the maintenance, growth and chemoresistance of many solid cancers including breast [120], lung [121], osteosarcoma [122], pancreatic [123] and melanoma [124] and is prognostic of worse overall and disease-free survival [122,123]. In all cases, CDK9 inhibition leads to the suppression of tumour formation and induces apoptosis via reduction of MCL-1 expression [84,[125][126][127][128].…”

Section: Bh3-mimetics and Oncogenic Kinasesmentioning

confidence: 99%

Targeting the BCL-2-regulated apoptotic pathway for the treatment of solid cancers

Fairlie

Lee

2021

Biochemical Society Transactions

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The deregulation of apoptosis is a key contributor to tumourigenesis as it can lead to the unwanted survival of rogue cells. Drugs known as the BH3-mimetics targeting the pro-survival members of the BCL-2 protein family to induce apoptosis in cancer cells have achieved clinical success for the treatment of haematological malignancies. However, despite our increasing knowledge of the pro-survival factors mediating the unwanted survival of solid tumour cells, and our growing BH3-mimetics armamentarium, the application of BH3-mimetic therapy in solid cancers has not reached its full potential. This is mainly attributed to the need to identify clinically safe, yet effective, combination strategies to target the multiple pro-survival proteins that typically mediate the survival of solid tumours. In this review, we discuss current and exciting new developments in the field that has the potential to unleash the full power of BH3-mimetic therapy to treat currently recalcitrant solid malignancies.

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Novel cyclin-dependent kinase 9 (CDK9) inhibitor with suppression of cancer stemness activity against non-small-cell lung cancer

Cited by 34 publications

References 54 publications

Targeting CDK9 for Anti-Cancer Therapeutics

Targeting CDK9 for Anti-Cancer Therapeutics

Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

Targeting the BCL-2-regulated apoptotic pathway for the treatment of solid cancers

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