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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Although the various stages of interphase are not usually distinguishable from a morphological perspective, each phase of the cell cycle has a set of distinct biochemical processes that prepare the cell for division. Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae. The CDK4/6 and CDK2 kinases are required for progression through G1 of the cell cycle and entry into S-phase, and control of these kinases occurs at multiple levels. The first level involves accumulation of the cyclin, the second is assembly into a cyclin-CDK complex, and the third is specific phosphorylation and dephosphorylation events. Additional regulation of G1 CDK activity is mediated by association with inhibitory proteins, the CKIs, that can physically block activation or block substrate/ATP access. The known CKIs are grouped into two gene families, Ink4 and Cip/Kip, according to their structural similarities. The D-type cyclins and their corresponding partner kinases CDK4 and CDK6 act as central integrators of extracellular signals and operate during the G1 phase of the cell cycle by phosphorylating the tumor-suppressor protein pRb, thus contributing to its inactivation. Mutations that can influence the function of cyclins CDK4 and CDK6, their regulating proteins, or pRB, can be found in most human tumors. Furthermore, cyclin D1 expression can be up-regulated by the Ras signaling pathway, which is itself up-regulated in many cancer cell types.
Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Alastair G. Stewart, Paul R. Tomlinson, Leslie Schachte
Cyclins have no intrinsic protein kinase activity, but function as regulatory elements of protein kinases known as Cdks.154 Cyclin D associates with Cdk4 or Cdk6.160–162 Cyclin E associates with Cdk2.163,164
Synthetic DNA-Based Compounds for the Prevention of Coronary Restenosis: Current Status and Future Challenges
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Andrew Zalewski, Yi Shi, John D. Mannion, Femando Roqué
The activation of cyclin dependent kinase 2 (cdk2) is required for the G1/S phase transition (Tsai et al., 1993). Although the levels of the p33cdk2 protein are constant throughout the cell cycle, cdk2 activity rises just a few hours prior to DNA synthesis (S phase). Surprisingly, cdk2 kinase activity is the highest at 14 days following vascular balloon injury (Abe et al., 1994), lagging behind the expected burst of cell proliferation in vivo (Clowes et al., 1983; Shi at al, 1996a). Notwithstanding the above, cdk2 antisense delivered in pluronic gel to the adventitia, or instilled into the lumen of denuded rat carotid arteries, resulted in the reduction of both cdk2 kinase activity and neointima (Abe et al., 1994; Morishita et al., 1994).
An introduction to the special issue of IJRB in honor of the extraordinary legacy of Professor John B. “Jack” Little in the radiation sciences
Published in International Journal of Radiation Biology, 2023
Amy Kronenberg, Edouard I. Azzam
Jack Little’s interest in the effects of ionizing radiation on cell cycle progression was pioneering. Using normal human cells, he firmly established, in 1968, the existence of the radiation-induced G1 cell cycle checkpoint. In subsequent decades and in work performed by Hatsumi Nagasawa, he went on to investigate this checkpoint in cancer cells that are wild-type or mutated for p53. Randi Syljuåsen, a post-doctoral fellow in the lab, built on this work and showed that loss of normal G1 checkpoint control is an early step in carcinogenesis that is independent of p53 status. In their article, Sissel Hauge and colleagues in Randi’s current laboratory in Oslo, Norway, review the expanding roles of cell cycle checkpoint inhibitors in radiation oncology, with a particular focus on the regulatory role of the WEE1, CHK1 and ATR. They describe in detail the biochemical events contributing to the inhibitory role of these kinases on activity of the cyclin-dependent kinases CDK1 and CDK2 during normal cell cycle progression and upon DNA damage. They describe the role that WEE1, CHK1 and ATR play in contributing to the radiation-induced G1 checkpoint promoted by the ATM-p53-p21Waf1 axis. They show how WEE1, CHK1 and ATR are essential in slowing down DNA replication in S phase in irradiated cells, and key to the radiation-induced G2 checkpoint.
Binding selectivity-dependent molecular mechanism of inhibitors towards CDK2 and CDK6 investigated by multiple short molecular dynamics and free energy landscapes
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Lifei Wang, Dan Lu, Yan Wang, Xiaoyan Xu, Peihua Zhong, Zhiyong Yang
Enhanced resistance to apoptosis and loss of cell-cycle regulation are principal hallmarks of cancers1. Cyclin-dependent kinases (CDKs), a family of 13 members containing CDK1-CDK132, are proline-directed serine-threonine kinases which related to an activating cyclin regulatory subunit3. CDK2 is an important macromolecule in cell cycle regulation, with taking part in inactivation and phosphorylation of the retinoblastoma protein (RB) tumour suppressor family and regulating both G1/S and G2/M progressions4,5. Furthermore, CDK2 strengthens DNA replication and plays a critical role in cell cycle in the DNA damage response6. CDK6 is regarded as a typical cell cycle kinase that boosts arrest of sensitive tumour cells in the G1 phase of the cell cycle. CDK6 takes part in the process of cancer development by using the kinase-dependent or non-kinase-dependent function7. Based on importance in promoting cancer initiation as well as progression, CDK2 and CDK6 have drawn intense interest as promising therapeutic targets for cancer.
Development of newly synthesised quinazolinone-based CDK2 inhibitors with potent efficacy against melanoma
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Eman R. Mohammed, Ghada F. Elmasry
Cyclin-dependent kinase 2 (CDK2) is a key regulator of the cell cycle transition and progression. CDK2 performs a critical role in controlling various events of the cell division cycle, such as DNA repair, gene transcription, G1-S transition, and modulation of G2 progression6–8. Additionally, the altered expression of cyclins whose association with CDKs is essential for their catalytic activity can drive aberrant proliferation in cancer. In the same vein, the overexpression of CDK2 regulatory subunits cyclin A and/or E is a key oncogenic process in many types of cancers9,10. Owing to the crucial role of CDK2 in cell cycle regulation, transcription activity, and tumours epigenetic modifications, CDK2 inhibition may confer a therapeutic benefit against certain cancers viz breast cancer11, colo-rectal cancer12,13, glioblastoma14–16, and melanoma17,18.