CDK7 in breast cancer: mechanisms of action and therapeutic potential

Gong, Ying; Li, Huiping

doi:10.1186/s12964-024-01577-y

Cited by 4 publications

(1 citation statement)

References 139 publications

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“…Currently, CDK7/9 inhibitors are attracting attention in breast cancer [ 10 , 12 , 36 ]. In particular, CDK7/9 are highly expressed in TNBC [ 12 , 28 , 37 , 38 , 39 , 40 ], and their combined expression is associated with poor prognosis [ 28 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation

Kwon,

Park,

et al. 2024

IJMS

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Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.

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Section: Introductionmentioning

confidence: 99%

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation

Kwon,

Park,

et al. 2024

IJMS

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Leveraging nuclear receptor mediated transcriptional signaling for drug discovery: Historical insights and current advances

Ben Patel,

Barnwal,

Saleh M. A.

et al. 2024

Advances in Protein Chemistry and Structural Biology

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A Robust Computational Framework for the Optimization of CDK7 Inhibitors as Promising Cancer Therapy

Shi,

Gao,

Buratto

et al. 2024

Preprint

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Cyclin-dependent kinase 7 (CDK7) plays a crucial role in cell cycle regulation and transcription, establishing it as a promising target for cancer therapy. Although the covalent inhibitor THZ1 effectively targets CDK7, it presents risks such as short half-life and potential off-target side effects. To address these limitations, we employed a computational workflow integrating virtual screening, molecular dynamics (MD) simulations, and free energy perturbation (FEP) method to design non-covalent CDK7 inhibitors with enhanced selectivity and safety profiles. MD simulations elucidated THZ1's inhibitory mechanism and identified key molecular fragments within its structure. By incorporating fragments from known inhibitors, we introduced extensive non-covalent interactions within the binding pocket, leading to the identification of three novel non-covalent inhibitors with binding affinities comparable to or higher than that of THZ1. Our findings not only introduce promising CDK7 inhibitors but also present a robust computational framework that could accelerate the discovery of kinase-targeted therapeutics.

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CDK7 in breast cancer: mechanisms of action and therapeutic potential

Cited by 4 publications

References 139 publications

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation

Leveraging nuclear receptor mediated transcriptional signaling for drug discovery: Historical insights and current advances

A Robust Computational Framework for the Optimization of CDK7 Inhibitors as Promising Cancer Therapy

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