Properties and Potential Applications of Chemical Inhibitors of Cyclin-Dependent Kinases

doi:10.1016/S0163-7258(98)00057-6

Pharmacology & Therapeutics

Volume 82, Issues 2–3, May–June 1999, Pages 279-284

https://doi.org/10.1016/S0163-7258(98)00057-6 Get rights and content

Abstract

Cyclin-dependent kinases (CDKs) trigger and co-ordinate the cell division cycle phases. They also play a role in neuronal cells and in the control of transcription. Intensive screening has led in the past few years to the identification of a series of chemical inhibitors of CDKs. Some of these compounds display remarkable selectivity and efficiency (IC₅₀ < 25 nM). Many have been co-crystallised with CDK2, and their atomic interactions with the kinase have been analysed in detail: all are located in the ATP-binding pocket of the enzyme. These inhibitors are antimitotic, they arrest cells in G1 and, at higher doses, in G2/M. Furthermore, they facilitate or even trigger apoptosis in proliferating cells. In contrast, they protect neuronal cells from apoptosis. The potential use of these inhibitors is being extensively evaluated in cancer chemotherapy (clinical trials, Phase I and II). Possible clinical applications are being investigated in other fields: cardiovascular (restenosis, tumoural angiogenesis, atherosclerosis), nephrology (glomerulonephritis), dermatology (psoriasis), parasitology (unicellular parasites such as Plasmodium, Trypanosoma, Toxoplasma, etc.), neurology (Alzheimer’s disease), viral infections (cytomegalovirus, human immunodeficiency virus, herpes). We anticipate the discovery of novel selective and powerful inhibitors in the near future, and hope for their efficient applications in various human diseases.

Introduction

The human genome is thought to encode about 2000 protein kinases. Among these, the cyclin-dependent kinases (CDKs), a family of 9 kinases (CDK1–9) activated by a family of cyclins (cyclin A–K, T), have been extensively studied because of their essential role in regulation of cell proliferation (CDK1, 2, 3, 4, 6, 7), of neural functions (CDK5), and of transcription (CDK7, 8, 9) (reviewed in Morgan 1997, Meijer et al. 1997b, Vogt and Reed 1998; see also http://www.sb-roscoff.fr/CyCell/Diapo/). The observation of numerous abnormal regulations of CDKs in human cancers has stimulated an active search for chemical inhibitors of these kinases (see reviews by Meijer 1996, Meijer and Kim 1997, Borgne and Meijer 1999). The first identified molecules display antimitotic and apoptosis-inducing properties, and are being evaluated as potential antitumour agents. However, numerous other therapeutic applications may also be worth investigating.

Section snippets

Chemical Variety, Efficiency, and Selectivity

The search for CDK inhibitors has mostly been based on the use of CDK1/cyclin B as a molecular target. Starfish oocytes have become a widely used source of purified enzyme because of the large quantities of these highly synchronous cells that can be prepared from mature animals, their exceptionally high content of CDK1/cyclin B, and the full activation of this kinase in M phase Rialet and Meijer 1991, Vesely et al. 1994, Meijer and Mordret 1994. Alternatively, recombinant CDKs have been

Potential therapeutic uses of cyclin-dependent kinase inhibitors

The first potential therapeutic use of CKIs that has been investigated is the treatment of cancer. CKIs indeed display a few encouraging properties in this regard:

1.
induction of apoptosis in dividing cells; facilitation of apoptosis by antitumour compounds (cis-platinum, mitomycin, etc.).
2.
clear antimitotic activity, with, for some compounds, a selectivity towards transformed versus normal cells. CGP60474, for example, arrests U2-OS cells in late G1, while it blocks U2-OS transformed by the Simian

Discussion

Only a few years have elapsed since the discovery of cdc2 in Schizosaccharomyces pombe by Nurse and Bissett (1981) to the identification of a human cdc2 homologue, CDK1 (Lee and Nurse, 1987), the use of CDK1/cyclin B as an enzymatic screening target (Rialet and Meijer, 1991), the identification of several potent inhibitors (Table 1), and the first clinical trials (Senderowicz et al., 1998). The therapeutic potentialities of CKIs extend much beyond the antitumour activity for which they were

Acknowledgements

We thank Armelle Jezequel for secretarial help. This work was supported by grants from the Association pour la Recherche sur le Cancer (ARC 9314) and the Conseil Régional de Bretagne.

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Properties and Potential Applications of Chemical Inhibitors of Cyclin-Dependent Kinases

Abstract

Introduction

Section snippets

Chemical Variety, Efficiency, and Selectivity

Potential therapeutic uses of cyclin-dependent kinase inhibitors

Discussion

Acknowledgements

Biol. Cell

Exp. Cell Res.

Blood

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Virology

J. Biol. Chem.

Parasitol. Today

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

Tetrahedron Lett.

Surgery

Blood

Bioorg. Med. Chem. Lett.

Biochem. Biophys. Res. Commun.

Neurobiol. Dis.

Trends Cell Biol.

Methods Enzymol.

Semin. Dev. Biol.

Exp. Cell Res.

Gene

Exp. Cell Res.

Mol. Cells

Bioorg. Med. Chem. Lett.

Exp. Cell Res.

Kidney Int.

Exp. Cell Res.

Cell

Involvement of RB kinases and phosphatases in life and death decisions

Oncol. Rep.

Flavopiridola cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells

Cancer Res.

Inhibiteurs chimiques des kinases cyclines-dépendantesrecherche et applications thérapeutiques potentielles

Médecine/Sciences

Cell cycle progression. New therapeutic target for vascular proliferative disease

Circulation

Cell cycle-independent induction of apoptosis by the anti-tumor drug flavopiridol in endothelial cells

Int. J. Cancer

Effects of olomoucine, a selective inhibitor of cyclin-dependent kinases, on cell cycle progression in human cancer cell lines

Anticancer Drugs

Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells

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Eur. J. Biochem.

Implication of cyclin-dependent kinases and glycogen synthase kinase 3 in the phosphorylation of microtubule-associated protein 1B in developing neuronal cells

J. Neurosci. Res.