CDK2

Official Full Name

cyclin dependent kinase 2

Organism

Homo sapiens

GeneID

1017

Background

This gene encodes a member of a family of serine/threonine protein kinases that participate in cell cycle regulation. The encoded protein is the catalytic subunit of the cyclin-dependent protein kinase complex, which regulates progression through the cell cycle. Activity of this protein is especially critical during the G1 to S phase transition. This protein associates with and regulated by other subunits of the complex including cyclin A or E, CDK inhibitor p21Cip1 (CDKN1A), and p27Kip1 (CDKN1B). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

Synonyms

CDKN2; p33(CDK2);

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Detailed Information

Cyclin-dependent kinases (CDKs) are well-known cell cycle regulators. CDKs are also targets of therapy and unexpected activation of CDKs may induce cancer proliferation. CDK2 is one of the most important CDKs. It combines with cyclin E and forms a complex. Cyclin E/CDK2 complex phosphorylates RB1 family and drives the cell cycle transition from G1 to S, which is directly related to the excessive proliferation of cancer cells. Furthermore, CDK2 has been described as a key regulator in cell cycle arrest upon DNA damage. Evidence suggests that the inhibition of CDK2 reduces proliferation in cancer, and CDK inhibitors are currently being evaluated in clinical trials.

Biological Functions of CDK2

CDK2 is one of the most important regulators for the transition and progression in a cell-division cycle. Progression through a cell-division cycle is regulated by the coordination of CDKs' activities in complex with their respective cyclin partner. When cells in the quiescent (G0) phase enters the cell cycle, extracellular signals modulate the activation of CDK4 or CDK6 by increasing the transcription of cyclin D. CDK4 or CDK6 can form active complex with D-type cyclin (D1, D2 and D3) to induce the phosphorylation of retinoblastoma protein (pRb, RB1). Hyperphosphorylation of pRb leads to the release of E2F and DP1 transcription factors which control the expression of genes required for G1/S transition and S phase progression. The CDK2-cyclin E complex is not only responsible for G1/S transition by upholding pRb's hyperphosphorylation, but also regulates centrosome duplication. Later, the activation of CDK2-cyclin A during early S-phase promotes the phosphorylations of various endogenous substrates to allow DNA replication and inactivation of G1 transcription factor E2F. Inactivation of E2F is important for S-phase completion while its existence in the absence of CDK2-cyclin A may result in cellular apoptosis. Thus, cytotoxicity can be achieved by inhibition of CDK2 instead of cell arrest.

CDK2 and Cancer

Cyclin dependent kinases play an important role in cell cycle regulation which makes them a promising target with multifarious therapeutic potential. CDK2 regulates various events of the eukaryotic cell division cycle, and the pharmacological evidences suggest that overexpression of CDK2 causes abnormal cell-cycle regulation, which is directly associated with hyperproliferation of cancer cells. It was observed that the ablation of CDK2 in p27Kip1 knockout mice do not have effects on tumor incidence, which shows that cells would be viable to grow independent of CDK2. On the other hand, p27Kip1 DK (Cip/Kip family, inhibitors of cell cycle) hinder cell division by disrupting the interactions of CDK2 with its partner cyclin E or A. In addition, either inactivation of its endogenous inhibitors (Cip-Kip) or inappropriate expression of CDK2 may cause various malignancies, including melanoma, osteosarcoma, lung carcinoma, pancreatic carcinoma, ovarian carcinoma, and sarcomas. Meanwhile, blocking CDK2 expression could be a good approach to avoid chemotherapy-induced alopecia by arresting the cell cycle without sensitization of the epithelium. Thus to decline CDK2 activity by potential lead compounds has proved to be an effective treatment for cancer.

Developing Effective Inhibitors of CDK2

For decades, CDK2 has been intensively investigated as a therapeutic target for cancer, and many inhibitors have surfaced out, which belong to the diverse scaffolds, including indazoles, thiazoles, isothiazoles, acylaminopyrazoles, cabolines, pyrimidines etc.

The involvement of CDK2 across numerous oncogenic pathways means that CDK2 inhibition has the potential to accentuate other therapies while also decreasing proliferation. Generally, the literature suggests that CDK2 inhibition can combine with different modalities of treatment, including radiotherapy, chemotherapy and targeted inhibitors. CDK2 inhibition appears to be effective in combination with a range of antimitotic chemotherapies. In triple-negative breast cancer (TNBC) cell lines, CDK2 inhibition (using CYC065) was combined with eribulin – a nontaxane microtubule inhibitor approved for metastatic breast cancer. In these circumstances, downregulation of CDK2 activity was associated with inhibition of the transforming growth factor (TGF)-β pathway, a major driver of proliferation in TNBC, resulting in restored chemosensitivity in resistant models. CDK2 inhibition has also been used in combination with targeted therapies, such as phosphoinositide 3 kinase (PI3K) inhibitors. Compared with single-agent treatment, the combination of CDK2 (CYC065: CDK2/5/9 inhibitor) with PI3K inhibition showed synergistic cytotoxicity in serous uterine carcinoma with CCNE1 amplification.

Figure 1. CDK2 inhibitors enhance the antiproliferative effects of PI3K/AKT/mTOR inhibitors. (Tadesse S, et al., 2020)

References:

Chohan T A, et al. Cyclin-dependent kinase-2 as a target for cancer therapy: progress in the development of CDK2 inhibitors as anti-cancer agents. Current medicinal chemistry, 2015, 22(2): 237-263.
Yin X, et al. Identification of CDK2 as a novel target in treatment of prostate cancer. Future Oncology, 2018, 14(8): 709-718.
Tadesse S, et al. Targeting CDK2 in cancer: challenges and opportunities for therapy. Drug Discovery Today, 2020, 25(2): 406-413.
Mahajan P, et al. Fusion of structure and ligand based methods for identification of novel CDK2 inhibitors. Journal of chemical information and modeling, 2017, 57(8): 1957-1969.

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