CDKs belong to the serine/threonine protein kinase family, and their kinase activity requires binding to cyclins. Abnormalities in CDKs have been reported to cause proliferation, genomic and chromosomal instability that lead to cancer and promote cancer progression and aggressiveness.
About CDK2
Similar to other protein kinases, CDK2 has a typical bilobed structure with N-terminal (residues 1-82) and C-terminal domain (residues 83-297). CDK2 provides adjacent binding sites for ATP and phosphorylated receptor protein substrates, making the γ-phosphate of ATP face the hydroxyl side chain of Ser/Thr on the substrate surface. In the absence of mitotic signaling, CDK2 is inactive. In late G1 phase, CDK2 activity increases because :(1) e2f-mediated transcription of CCNE gene, whose protein products bind and activate CDK2; (2) Isolation of CDK4/6-cyclin D-mediated interacting protein/kinase inhibitor (Cip/Kip) from CDK inhibitors p21Cip1, p27Kip1, and p57Kip2CDK. These inhibitors bind to and inactivate CDK2-cyclin complex; (3) Cip/Kip ubiquitin-mediated proteolysis after CDK2 phosphorylation.
The functions of CDK2
1)Regulate cell cycle and DNA replication
CDK2 is a core cell cycle regulator during cell division, which is active from late G1 phase to the entire S phase. CDK2 is activated by binding to cyclin E1 or E2, cyclin A2, and by CAK complex (CDK7, MAT1, cyclin H) phosphorylation and by removing CDC25A inhibition of phosphorylation. CDK2 also phosphorylates several components of the prereplication complex, which is required to initiate DNA synthesis.
2)Regulate DNA damage response (DDR)
Following DNA damage, DDR arrests cells at G1/S phase to repair damaged DNA and maintain genomic fidelity in daughter cells. Two mechanisms of the G1/S DNA damage checkpoint inhibit proliferation through CDK2. Targeting CDC25A for degradation leads to sustained inhibition of phosphorylation at CDK2 Thr14 and Tyr15 by WEE1, thereby blocking its entry into S phase.
3)Regulate apoptosis
CDK2 regulates the core regulatory and functional components of the apoptotic pathway. CDK2 target protein FOXO1 plays an important role in triggering DNA damage-induced apoptosis after dsDNA disruption. CDK2 also prevents apoptosis by phosphorylating the pro-survival factor myeloid leukemia cell differentiation protein (MCL-1).
Biomarkers of CDK2 activity
1)Changes in cyclin-CDK complex
The major regulators of CDK2 activity are the cyclins to which it binds: cyclin E1, cyclin E2, cyclin A1 and cyclin A2, and the cyclin-dependent kinase inhibitors of the cyclin-CDK2 complex: p21, p27, and p57.
2)Modification of cyclin-CDK complex
CDK2 is a pathway that increases growth factor signaling during cell cycle progression and is a target of PI3K/AKT pathway. AKT phosphorylates CDK2 at Thr39 in late S and late G2, leading to its cytoplasmic translocation into the G2/M phase. CDK2 is also activated by CAK : CDK7, cyclin H, and MAT1, that is, inhibitory Tyr15 phosphorylation is removed by adding Thr160 phosphorylation and CDC25A phosphatase.
The main motivation for the development of CDK2 inhibitors is their potential application as anti-cancer drugs, and small molecule CDK2 selective inhibitors will be important chemical probes for dissecting the cellular processes or the basis of disease. Since the 1990s, the development of CDK2 inhibitors has entered the clinical stage, but almost all of them are multi-target inhibitors.
1) Dinaciclib (Phase III)
Developed by Merck, a CDK1/2/5/9 inhibitor, is currently in phase III clinical treatment for refractory chronic lymphocytic leukemia. In 2011, the FDA granted orphan drug status to dinaciclib for the treatment of CLL. The results of clinical studies have shown that dinaciclib is well tolerated in combination with rituximab in patients with relapsed chronic lymphocytic leukemia.
2) Seliciclib (Phase II)
Developed by Cyclacel Pharmaceuticals, a lead compound of the CYC-200 series of oral small molecule cyclin-dependent kinase (CDK1/2/5/7) inhibitors, is currently in clinical phase II for the treatment of B-cell lymphoblastic leukemia. Combined with gemcitabine/cisplatin as first-line therapy for non-small cell lung cancer. The company is also investigating the drug as a potential treatment for inflammation associated with SARS-CoV-2 infection (COVID-19).
3) Pf-07104091 (Phase I/II)
Developed by Pfizer, it is a selective inhibitor of CDK2 that is used orally for the treatment of various cancers, including breast cancer, small cell lung cancer, non-small cell lung cancer, and ovarian cancer. In April 2021, preclinical data were presented at the 112th annual meeting of the AACR to show that the drug can be used to treat various tumor models.
4) Ebvaciclib (Phase I/II)
Developed by Pfizer, it is a CDK2/4/6 inhibitor. The binding affinity of ebvaciclib to CDK2, 4, 5 and 6 is 40 times higher than that of off-target CDK1 and CDK9.
5) Fadraciclib (Phase I)
Developed by Cyclacel Pharmaceuticals, it is a CDK2/9 inhibitor administered intravenously for the treatment of advanced cancers, including chronic lymphocytic leukemia, acute myeloid leukemia, and myelodysplastic syndromes.
6)Nuv-422 (Phase I/II)
Developed by Nuvation Bio, it is a CDK2/4/6 inhibitor being developed clinically for the treatment of glioma. In November 2020, a phase I/II trial for adult patients with relapsed or refractory high-grade glioma was initiated; In February 2021, the company planned to initiate phase I trials in brain metastases, followed by phase I trials in estrogen receptor-positive metastatic breast cancer, and then phase I trials in metastatic castration-resistant prostate cancer.
Conclusion
To date, there are very few CDK inhibitors on the market (only four, all of them CDK4/6 inhibitors), and the large family with relatively clear functions has great potential for future drug development.
Related Targets:
| Targets | Description |
| CDK | Cyclin dependent kinases (CDKs) play a major role in many cellular processes including the mammalian cell cycle. |
Related Products:
| Name | CAS | Synonyms | Description |
| Dinaciclib | 779353-01-4 | SCH 727965; PS 095760; 2-[(2S)-1-[3-ethyl-7-[(1-oxidopyridin-1-ium-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-2-yl]ethanol | Dinaciclib is a potent CDK inhibitor with potential antineoplastic activity. |
| Seliciclib | 186692-46-6 | CYC 202; R-Roscovitine; Roscovitin; Roscovitine; | Seliciclib is an orally bioavailable, small-molecule cyclin-dependent kinase (CDK) inhibitor with potential proapoptotic and antineoplastic activities. |