Therapeutic targeting of transcriptional cyclin-dependent kinases

Galbraith, Matthew D.; Bender, Heather; Espinosa, Joaquín M.

doi:10.1080/21541264.2018.1539615

Cited by 83 publications

(97 citation statements)

References 147 publications

(215 reference statements)

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“…When the initiating transcription occurs, the Ser5 phosphorylation level decreases, while Ser2 and Tyr1 phosphorylation increases to promote transcriptional elongation. During transcription termination, Tyr1 is dephosphorylated firstly, closely followed by Ser5, Ser7, and Ser2, which permits restarting the transcription cycle [39].…”

Section: The Roles Of Cdks In Transcriptionmentioning

confidence: 99%

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Ding

Cao

Lin

et al. 2020

IJMS

347

216

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Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

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Section: The Roles Of Cdks In Transcriptionmentioning

confidence: 99%

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Ding

Cao

Lin

et al. 2020

IJMS

347

216

View full text Add to dashboard Cite

show abstract

“…In general, most cancer cells exhibit defects in cell cycle regulation and gene transcription, which promotes uncontrolled cell proliferation leading to tumorigenesis [9]. Cyclin-dependent kinases (CDKs) are members of the serine/threonine protein kinase family and are involved in cell cycle control and transcription regulation, which play central roles in tumorigenesis [10,11].…”

Section: Introductionmentioning

confidence: 99%

“…In tumorigenesis, CDK7 encourages tumor growth by directly linking transcription regulation to cell cycle control. Based on these molecular traits, CDK7 has emerged as an attractive target for novel anti-neoplastic treatments in various cancers, including EOC [8,9]. THZ1, a covalent CDK7 inhibitor, was first described as an antineoplastic agent in T-cell acute lymphoblastic leukemia [13].…”

Section: Introductionmentioning

confidence: 99%

CDK7 is a reliable prognostic factor and novel therapeutic target in epithelial ovarian cancer

Kim

Cho

Ryu

et al. 2020

Gynecologic Oncology

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“…Due to its activity in transcription and cell cycle regulation, the human CAK plays an important role in regulating cell growth and division. Consequently, inhibition of the CAK has been found to be a promising strategy for treatment of proliferative diseases (Galbraith et al, 2019;Kwiatkowski et al, 2014). To obtain insight into the covalent binding of the cysteine-reactive anti-cancer compound THZ1 (Kwiatkowski et al, 2014) to CDK7 within the CAK, we have determined the 3.4-Å-resolution structure of THZ1 bound to a CDK7-cyclin H-MAT1D219 complex (CAK-MAT1D219), in which the N-terminal region of MAT1, including its RING domain, has been removed ( Fig.…”

Section: Structural Mechanism Of Irreversible Inhibition Of Cdk7 By Thz1mentioning

confidence: 99%

“…This process is not only important for normal transcription, but also contributes to aberrantly elevated transcription levels in cancer cells. Consequently, transcription-related CDKs have been identified as promising drug targets (Galbraith et al, 2019), and inhibition of CDK7 by compounds such as THZ1 or SY-1365 has been shown to selectively kill cancer cells that require elevated levels of transcription (Hu et al, 2019;Kwiatkowski et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

The cryo-electron microscopy structure of the human CDK-activating kinase

Greber

Perez-Bertoldi

Lim

et al. 2020

Preprint

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The human CDK-activating kinase (CAK), a complex composed of cyclin dependent kinase (CDK) 7, cyclin H, and MAT1, is a critical regulator of transcription initiation and the cell cycle. It acts by phosphorylating the Cterminal heptapeptide repeat domain of the RNA polymerase II subunit Rpb1, which is an important regulatory event in transcription initiation by Pol II, and it phosphorylates the regulatory T-loop of CDKs that control cell-cycle progression. Here, we have determined the three-dimensional structure of the catalytic module of human CAK, revealing the structural basis of its assembly and providing insight into CDK7 activation in this context. The unique third component of the complex, MAT1, substantially extends the interaction interface between CDK7 and cyclin H, explaining its role as a CAK assembly factor, and it forms interactions with the CDK7 T-loop, which may contribute to enhancing CAK activity. We have also determined the structure of the CAK in complex with the covalently bound inhibitor THZ1 in order to provide insight into the binding of inhibitors at the CDK7 active site and aid in the rational design of therapeutic compounds. SignificanceControl of gene expression and the cell cycle is critical for appropriate cell growth and timely cell division. Failure of the mechanisms regulating these processes can result in proliferative diseases. A molecular complex termed the CDK activating kinase (CAK) impinges on both of these regulatory networks in human cells and is thus a possible drug target for treatment of cancer. Here, we use cryo-electron microscopy to describe the detailed molecular structure of the human CAK, revealing its architecture and the interactions between its regulatory elements. Additionally, we have obtained the structure of the CAK in complex with a small-molecule inhibitor.

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Therapeutic targeting of transcriptional cyclin-dependent kinases

Cited by 83 publications

References 147 publications

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

CDK7 is a reliable prognostic factor and novel therapeutic target in epithelial ovarian cancer

The cryo-electron microscopy structure of the human CDK-activating kinase

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