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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
In order to divide successfully, a cell must copy its DNA so that each daughter cell receives its full set of chromosomes. This is achieved by a tightly regulated mitosis following the cell cycle pathway (Figure 2.6). Passage through the cell cycle is controlled by cyclin proteins, in a cascade of phosphorylation events. Each cyclin acts as a catalytic subunit in partnership with a cyclin-dependent kinase (CDK). Upon cyclin binding, CDKs phosphorylate target proteins that are required for cell-cycle progression. CDK-specific inhibitors (CDKIs) bind cyclin–CDK complexes to regulate their activity and can themselves be regulated by other proteins. During mitosis, one member of each chromosome pair becomes attached to a centriole. Centrioles move to opposite ends of the cell, taking the chromosomes with them. In order to prevent inappropriate proliferation of cells, mitosis is tightly controlled, with various checkpoints to ensure that every part of the mitotic process is completed correctly before the next stage begins. Because uncontrolled proliferation is a hallmark of cancer, the cell cycle provides an obvious target for therapy. CDKIs often act as tumour suppressors and are potentially useful anticancer agents.
The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Among the mechanisms in place to control the cell cycle are cascades involving a variety of proteins called cyclins, along with enzymes called cyclin-dependent kinases (CDK). Different types of each are responsible for the regulation of the different phases of the cell cycle. Binding of a cyclin with its enzyme activates the enzyme and serves to move the cell cycle from one phase to the next. Progression through the cell cycle is regulated by sequential activation of cyclins and CDKs. The process can also be down-regulated by CDK inhibiters.
Role of Plant-Based Bioflavonoids in Combating Tuberculosis
Published in Megh R. Goyal, Durgesh Nandini Chauhan, Assessment of Medicinal Plants for Human Health, 2020
Alka Pawar, Yatendra Kumar Satija
Various reports have highlighted the role of flavonoids in chemoprevention. Cyclins and cyclin-dependent kinases (CDKs) are two types of regulatory molecules involved in the cell cycle progression. Activation of CDKs in an uncontrolled manner can lead to cancer. Therefore, to check this process, massive research has been focused on substances that can prevent or control CDKs activation. Many different flavonoids exhibited such activity, such as genistein, quercetin, daidzein, luteolin, kaempferol, apigenin, and epigallocatechin.24
Design, synthesis and molecular docking of new fused 1H-pyrroles, pyrrolo[3,2-d]pyrimidines and pyrrolo[3,2-e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Amany Belal, Nagwa M. Abdel Gawad, Ahmed B. M. Mehany, Mohammed A. S. Abourehab, Hazem Elkady, Ahmed A. Al‐Karmalawy, Ahmed S. Ismael
The cyclin-dependent kinases (CDKs) are a group of enzymes involved in cell cycle progression and cellular proliferation24. They work by phosphorylating critical serine and threonine residues in host proteins, which then can activate them25,26. It is commonly believed that inhibiting CDKs could help the limitation of the uncontrolled cellular proliferation seen in some malignancies27. The majority of CDK inhibitors bind to the ATP pocket as ATP-competitive inhibitors with essential structural hydrogen-bonding motifs28. Cyclin-dependent kinase 2 (CDK2) belongs to the serine/threonine protein kinase family, and the CDK2 activity is found to be typically high in different types of human cancers. Studies have reported that CDK2 overexpression indicates poor prognosis in patients with HCC, and inhibition of CDK2 activity could reverse the malignant phenotype of cancer cells. Many studies revealed a key role of CDK2 in EGF-induced cell transformation and the associated signal transduction pathways29. The literature survey revealed that EGFR and CDK2 were the key targets for many antitumor agents e.g. cinobufagin30. In addition, biological and computational evidence supported that anticancer agents such as benzamide-substituted chalcones exerted their anti-proliferative effects via dual EGFR/CDK2 inhibitory activities31.
Identification of novel CDK2 inhibitors by a multistage virtual screening method based on SVM, pharmacophore and docking model
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Jing-Wei Liang, Ming-Yang Wang, Shan Wang, Shi-Long Li, Wan-Qiu Li, Fan-Hao Meng
Cyclin-dependent kinases are the family of Ser/Thr protein kinases that are essential in regulating cell progression through cell cycle G/S and G2/M1–3. The activities of cyclin-dependent kinases are regulated by the regulatory subunits of the complex cyclins and phosphorylation. Cyclin E binds G1 phase CDK2, which is required for the transition from G1 to S phase, while binding with Cyclin A is required to progress through the S phase2,3. The precise regulation of CDK activity is essential for the stepwise execution of the many processes required for cell growth and division, including DNA replication and chromosome separation4,5. Abnormal CDK control of the cell cycle has been strongly linked to the molecular pathology of cancer, and CDK2 is now thought to be dispensable for tumour formation and maintenance5,6. Additionally, increasing studies have shown that inhibition of CDK2 could induce cancer cell apoptosis with no damage to normal cells6. Therefore, CDK2 is an attractive target for the development of a novel anticancer agent7.
Novel [(N-alkyl-3-indolylmethylene)hydrazono]oxindoles arrest cell cycle and induce cell apoptosis by inhibiting CDK2 and Bcl-2: synthesis, biological evaluation and in silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Tarfah Al-Warhi, Mahmoud F. Abo-Ashour, Hadia Almahli, Ohoud J. Alotaibi, Mohammad M. Al-Sanea, Ghada H. Al-Ansary, Hanaa Y. Ahmed, Mahmoud M. Elaasser, Wagdy M. Eldehna, Hatem A. Abdel-Aziz
Cyclin-dependent kinases (CDKs) are considered as crucial factors that affect diverse key transitions in cell cycle for the cancer cell, in addition to regulation of apoptosis, transcription and exocytosis, therefore therapeutic strategies based on inhibition of CDKs stand out as a promising opportunity for anticancer drug discovery and an efficient approach for management of different human malignancies. On the other hand, apoptosis, an automatic cancer cell death, was found as an important consequence of CDKs inhibition and can be assessed by cell cycle arrest at low concentration or even mitochondrial damage at high concentration1. This fact was discovered from previous studies on CDKs inhibitors as Roscovitine and Purvalanol and their effect on three different prostate cancer cell lines2. In addition, the link between CDKs and apoptosis was revealed in the investigational research of the effect of Ibulocydine, a prodrug CDK inhibitor, on hepatocellular carcinoma3.