CDK7

Official Full Name

cyclin dependent kinase 7

Organism

Homo sapiens

GeneID

1022

Background

The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression. This protein forms a trimeric complex with cyclin H and MAT1, which functions as a Cdk-activating kinase (CAK). It is an essential component of the transcription factor TFIIH, that is involved in transcription initiation and DNA repair. This protein is thought to serve as a direct link between the regulation of transcription and the cell cycle. [provided by RefSeq, Jul 2008]

Synonyms

CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15;

Bio Chemical Class

Kinase

Protein Sequence

MALDVKSRAKRYEKLDFLGEGQFATVYKARDKNTNQIVAIKKIKLGHRSEAKDGINRTALREIKLLQELSHPNIIGLLDAFGHKSNISLVFDFMETDLEVIIKDNSLVLTPSHIKAYMLMTLQGLEYLHQHWILHRDLKPNNLLLDENGVLKLADFGLAKSFGSPNRAYTHQVVTRWYRAPELLFGARMYGVGVDMWAVGCILAELLLRVPFLPGDSDLDQLTRIFETLGTPTEEQWPDMCSLPDYVTFKSFPGIPLHHIFSAAGDDLLDLIQGLFLFNPCARITATQALKMKYFSNRPGPTPGCQLPRPNCPVETLKEQSNPALAIKRKRTEALEQGGLPKKLIF

Open

Disease

Breast cancer, Lung cancer, Malignant haematopoietic neoplasm, Nasopharyngeal cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

7 +

Discontinued Drug

2 +

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Detailed Information

An important member of the CDK family, Cyclin-Dependent Kinase 7 (CDK7) has encoding genes generated from substantially comparable gene products of the Saccharomyces cerevisiae CDC28 gene and the Schizosaccharomyces pombe CDC2 gene. Multifunctionality in cell cycle and gene transcription control is well known in CDK7. Being a serine/threonine kinase, CDK7 forms a trimeric complex with Cyclin H and MAT1 to become a CDK-activating kinase (CAK), which is very essential in two fundamental biological processes: cell cycle and transcription initiation. While MAT1 improves function by stabilizing the complex and attaching it to the transcription factor TFIIH in humans, the kinase activity of CDK7 depends on the binding of Cyclin H.

The specialty of CDK7 is its dual function as a fundamental node in the cell cycle regulating network and a major actor in RNA polymerase II (Pol II)-mediated transcription start. This dual ability gives CDK7 a unique role in preserving normal cellular activities and helping diseases to arise.

Core Regulatory Role of CDK7 in the Cell Cycle

The cell cycle moves in an ordered sequence depending on the coordinated activity of many CDKs; CDK7, a kinase-activating agent, is very essential in this process. By T-loop phosphorylation, CDK7 activates downstream enzymes including CDK1, CDK2, CDK4, and CDK6, hence guiding the change in major phases of the cell cycle. For instance, by activating CDK4/6 and then driving entrance into the S phase by activating CDK2, thus completing the commencement of DNA replication; simultaneously, CDK7 controls the change from G2 to M phase by stimulating CDK1, so assuring smooth cell division. These systems not only guarantee exact control of the cell cycle but also provide adaptive flexibility in response to DNA damage and outside pressure.

In particular, CDK7's expression and activity stay constant during the cell cycle, which emphasizes its central role as the "scheduler" in cell cycle control. Because of its stability, CDK7 is a target of great relevance for research on disorders of the cell cycle.

Figure 1 provides an overview of the cell cycle, detailing the activation of key cyclin-CDK complexes, their role in triggering DNA replication and cell cycle transitions, and the regulation of these processes by various proteins and phosphorylation events. Figure 1. Overview of the cell cycle. (Cheng W, et al., 2019)

Dual Functions of CDK7 in Gene Transcription

Apart from its vital role in the cell cycle, CDK7, as part of the TFIIH complex, also plays an equally important role in gene transcription. At active gene promoters, CDK7 phosphorylates the S5 and S7 sites of the C-terminal domain (CTD) of Pol II, triggering transcription initiation and facilitating the transcription elongation process. Moreover, CDK7 indirectly regulates CTD's S2 site phosphorylation by activating CDK9, further enhancing the precision of transcription regulation. This collaborative action ensures efficiency and accuracy in the transcription process and maintains normal physiological functions of the cell.

CDK7's role is particularly prominent in genomic stress responses. When DNA damage occurs, CDK7 phosphorylates and activates p53, triggering cell cycle arrest or apoptosis, thereby helping cells recover or eliminate damaged cells. This feedback mechanism further highlights CDK7's key role in maintaining genomic stability.

Relationship between CDK7 and Cancer

The beginning and spread of different malignancies is intimately related to abnormal expression or malfunction of CDK7. For oral squamous cell carcinoma and triple-negative breast cancer, for example, overexpression of CDK7 greatly increases the proliferative and invasive power of cancer cells. By encouraging aberrant transcription and cell cycle control in cancer cells, therefore enabling the continuous development of tumors, CDK7 also helps to shape the tumor microenvironment. Hence, CDK7 is seen as a possible target for anti-cancer treatment.

Progress in Drug Development Targeting CDK7

Since CDK7 is so important for cancer, it has taken the front stage in recent years of therapeutic research. Although early CDK inhibitors such as Alvocidib could generally block many CDKs, limited selectivity caused disappointing therapeutic effectiveness. Researchers have created a suite of highly selective CDK7 inhibitors to improve treatment effectiveness. For instance, THZ1, a covalent small molecule inhibitor aiming at the ATP-binding site of CDK7, has demonstrated amazing anti-tumor action in gliomas, ovarian cancer, and cervical cancer among other tumors.

Moreover, the special ability of THZ1 to pass the blood-brain barrier gives fresh hope for the treatment of brain malignancies. Researchers have produced a variety of more effective and stable derivatives and thoroughly refined the structure of THZ1 in response to possible resistance problems.

Targeting several solid cancers including breast cancer, ovarian cancer, and non-Hodgkin's lymphoma, many CDK7 inhibitors—including CT7001, SY-5609, SY-1365, and BTX-A51—have reached clinical research stages with great promise. Especially in Phase I and Phase II clinical studies for breast and ovarian cancer, SY-5609 and SY-1365 have shown notable anti-tumor effects, therefore supporting CDK7-targeted treatment approaches.

References:

Sánchez-Martínez C, Lallena MJ, et al. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015-2019). Bioorg Med Chem Lett. 2019;29(20):126637.
Cheng W, Yang Z, et al. Recent development of CDK inhibitors: An overview of CDK/inhibitor co-crystal structures. Eur J Med Chem. 2019;164:615-639.
Suski JM, Braun M, et al. Targeting cell-cycle machinery in cancer. Cancer Cell. 2021;39(6):759-778. 4.
Teng Y, Lu K, Zhang Q, et al. Recent advances in the development of cyclin-dependent kinase 7 inhibitors. Eur J Med Chem. 2019;183:111641.

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